{"APPLICATION_ID":"8693991","ABSTRACT_TEXT":"Methamphetamine (MA) is remarkably addictive and relapse to excessive use is highly probable and poses serious health concerns. Genetic factors have been little studied with regard to their role in susceptibility to MA addiction or relapse. A key goal will be to utilize a validated animal model of genetically-determined high and low susceptibility to MA use to improve genetic mapping resolution and to study an already identified neuroimmune gene network that influences MA response in this genetic model. In Aim 1, in coordination with Animal Core 3, replicated sets of selected mouse lines bred for high and low voluntary consumption of MA will be produced and QTL mapping will be performed by the Biostatistics and Genetics Core 2. These mice will be used for studies proposed in Components 7, 8 and 9. In Aim 2, neurocircuitry will be examined in the selected lines, using cFos mapping after acute and repeated MA treatment, and these data will be used to identify brain regions for immune factor analysis, and will be compared to imaging results from Scientific Component 7 for brains from the MA consumption selected lines. In Aim 3, qPCR immunology arrays will be used to examine brain and peripheral blood mononuclear cell gene expression for immune specific genes using samples from selectively bred MA drinking line mice that have been acutely or repeatedly treated with MA or with saline, or are in \"remission\". These data will be used in additional network analysis by the Biostatistics and Genetics Core 2 and compared to human peripheral gene expression results for controls, chronic MA users and user in remission. In Aim 4, cognitive, anxiety-like, and impulsivity-like traits will be examined in drug naive, acute, and repeated MA-exposed MADR mice, as well as mice in remission from MA exposure. Tissue from mice treated in the same way will be transferred to Translational Service Core 5 for analysis of immune factors and to Component 7 for imaging;half of each brain will be sent for each purpose to allow individual animal correlations to be performed. These data will also be examined for correspondence between behavior, neurocircuitry and immune system alterations. In addition, impulsivity-like measures in mice will be compared to similar measures in humans from Component 7. Finally, data collected in Component 9 will inform Component 8, with regard to traits and which of the selected lines to be studied for immunotherapeutic intervention. Cross-species analyses across components will identify key immune factors associated with chronic MA exposure (and remission) and MA-induced neuropsychiatric impairments, with the goal of ultimately identifying novel immunotherapeutic interventions.","ACTIVITY":"P50","ADMINISTERING_IC":"DA","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"06/30/2014","BUDGET_START":"07/01/2014","BUDGET_END":"06/30/2015","CFDA_CODE":"","CORE_PROJECT_NUM":"P50DA018165","ED_INST_TYPE":"","FOA_NUMBER":"PAR-10-189","FULL_PROJECT_NUM":"5P50DA018165-08","FUNDING_ICs":"NIDA:212488\\","FUNDING_MECHANISM":"Research Centers","FY":"2014","IC_NAME":"NATIONAL INSTITUTE ON DRUG ABUSE","NIH_SPENDING_CATS":"","ORG_CITY":"PORTLAND","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"03","ORG_DUNS":"","ORG_FIPS":"","ORG_NAME":"OREGON HEALTH &SCIENCE UNIVERSITY","ORG_STATE":"OR","ORG_ZIPCODE":"","PHR":"Many individuals try MA, but only some become addicted and continue to use MA even though it has profoundly adverse effects on their health and relationships. Genetic differences could influence who is at greater risk for developing MA addiction. If the important genetic pathways were known, researchers and clinicians would be better able to develop treatments for the prevention and treatment of MA addiction.","PI_IDS":"1910136;","PI_NAMEs":"PHILLIPS, TAMARA J;","PROGRAM_OFFICER_NAME":"","PROJECT_START":"","PROJECT_END":"","PROJECT_TERMS":"Acute;Adverse effects;Animal Model;Animals;Anxiety;Behavior;Behavioral;Behavioral Genetics;Biometry;Blood specimen;Brain;Brain region;brain tissue;Breeding;Chromosome Mapping;Chronic;Cognitive;Consumption;Data;discounting;Disease remission;DNA;drinking;Exhibits;Factor Analysis;Fibrinogen;Gene Expression;Gene Expression Profiling;Genes;Genetic;Genetic Models;Goals;Health;Human;human subject;Image;Immune;Immune system;Immunology;Immunotherapeutic agent;Immunotherapy;Impairment;improved;Impulsivity;Individual;Intake;Intervention;Location;Maps;Measures;Methamphetamine;methamphetamine abuse;Methamphetamine dependence;methamphetamine exposure;Methods;Modeling;Motivation;Mus;neuroadaptation;Neurocognitive;neuroimaging;neuropsychiatry;novel;Oral;Outcome;Pathway Analysis;Pathway interactions;Pattern;Peptides;Peripheral;Peripheral Blood Mononuclear Cell;Pharmaceutical Preparations;Phenotype;Potassium Chloride;Predisposition;preference;Prevention;Quantitative Trait Loci;Quinine;Recording of previous events;Regimen;Regulation;Relapse;relating to nervous system;Research;Research Personnel;Resolution;response;Rewards;Risk;Role;Route;Saccharin;Saline;Sampling;Self Administration;Self-Administered;Services;Signal Transduction;Sodium Chloride;Taste Perception;Testing;Tissue Sample;Tissues;trait;Water","PROJECT_TITLE":"Genetic and Neuroimmunological Factors in Methamphetamine Addicition","SERIAL_NUMBER":"18165","STUDY_SECTION":"ZDA1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"6488","SUFFIX":"","SUPPORT_YEAR":"8","TOTAL_COST":"","TOTAL_COST_SUB_PROJECT":"212488"}
{"APPLICATION_ID":"8693362","ABSTRACT_TEXT":" Project Summary Risk bimarkers have become increasingly important in clinical decision making, guiding patients and their clinicians in choosing the most appropriate course of therapy or surveillance after treatment. Constructing accurate and individualized prediction rules and conducting rigorous validation are critical to the cancer biomarker field. Prospective cohort studies are crucial for such evaluation as time to event carries more information about a marker's value on early detection and prognosis than a simple measure of disease status. But prospective biomarker evaluation is challenging. Until now there has been little guidance pro- vided for statistical design and analysis of these studies. We propose to extend our previously funded effort to address several new challenges in prospective marker evaluation. The proposal will emphasize three unique aspects in prospective biomarker evaluation. First, for many cancers disease outcome may be heterogeneous due to the biological nature of the disease or selection of treatments. Constructing and validating prognostic and treatment selection rules based on more specific prediction of the risk of develop- ing aggressive cancer as opposed to indolent cancer is of great clinical interest yet analytically challenging. In Aim 1 we will provide statistical tools for developing and validating risk markers in a population with an unknown mixture of indolent and aggressive cancers. We propose statistical methods that facilitate the development and evaluation of prognostic markers for risk stratification. Methods for deriving and evalu- ating individualized treatment rules in the presence of a mixture of indolent and aggressive cancers will be considered. Second, among patients diagnosed with cancer who chose to be on active surveillance, developing monitoring tools to make adaptive monitoring or intervention recommendations with longitudinal biomarkers may alleviate overtreatment without missing signs of progression. In Aim 2 we will consider flexible procedures to quantify the updated predictive accuracy of longitudinal markers. In addition, we will develop and evaluate decision rules on the basis of risk, incorporating both cross-sectional and longi- tudinal marker information. The ascertainment of marker information in a large cohort requires enormous resources. Cost-effective cohort sampling is therefore highly desirable. In Aim 3 we will develop procedures to improve the efficiency of estimating risk and accuracy parameters and rigorously evaluate and compare different choices of matching/stratification rules and identify optimal pairs of analyses and sampling strate- gies. We will also develop estimation procedures for evaluating longitudinal markers in two-phase studies. Applications in cancer biomarker development provide a context for our research. Data from the Early De- tection Research Network and from several large cohort studies will be analyzed. Programs and algorithms developed in this proposal will be made available to public.","ACTIVITY":"R01","ADMINISTERING_IC":"GM","APPLICATION_TYPE":"2","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"05/27/2014","BUDGET_START":"06/01/2014","BUDGET_END":"04/30/2015","CFDA_CODE":"859","CORE_PROJECT_NUM":"R01GM085047","ED_INST_TYPE":"","FOA_NUMBER":"PA-11-260","FULL_PROJECT_NUM":"2R01GM085047-05","FUNDING_ICs":"NIGMS:326324\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES","NIH_SPENDING_CATS":"","ORG_CITY":"SEATTLE","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"FRED HUTCHINSON CANCER RESEARCH CENTER","ORG_STATE":"WA","ORG_ZIPCODE":"981091024","PHR":"PUBLIC HEALTH RELEVANCE: The research proposal addresses the pressing need for strong statistical input in the cancer biomarker field, providing comprehensive statistical tools that will enable investigators to conduct valid and more powerful biomarker validation studies and to evaluate the prognostic and treatment-selection potential of novel biomarkers. Integrating our research into clinical settings will help improve survival outcomes and reduce the burden of cancer treatment.            ","PI_IDS":"8572341;","PI_NAMEs":"ZHENG, YINGYE;","PROGRAM_OFFICER_NAME":"LYSTER, PETER ","PROJECT_START":"09/04/2009","PROJECT_END":"04/30/2018","PROJECT_TERMS":"Address;Aftercare;Algorithms;base;Biological;Biological Markers;Breast Cancer Detection;cancer therapy;case control;Clinical;clinical decision-making;clinical risk;cohort;Cohort Studies;Computer software;cost effective;Data;Decision Making;design;Development;Diagnosis;Disease;Disease Outcome;Early Diagnosis;Evaluation;Event;flexibility;Funding;Future;Goals;Guidelines;Hepatitis C;improved;Indolent;interest;Intervention;malignant breast neoplasm;Malignant neoplasm of prostate;Malignant Neoplasms;Measurement;Measures;Methods;Modeling;Monitor;Nature;Noninfiltrating Intraductal Carcinoma;novel;Outcome;outcome forecast;Patients;Phase;Population;Population Surveillance;Predictive Value;Primary carcinoma of the liver cells;Procedures;prognostic;Prognostic Marker;programs;prospective;public health relevance;Recommendation;Research;Research Personnel;Research Proposals;Resources;Risk;Risk Estimate;Risk Factors;Risk Marker;Rules of conduct;Sampling;Selection for Treatments;Staging;Statistical Methods;Stratification;Surveillance Program;Survivors;System;Techniques;Testing;Time;tool;Update;user-friendly;Validation;validation studies","PROJECT_TITLE":"Statistical Methods for Prospective Evaluation of Biomarkers","SERIAL_NUMBER":"85047","STUDY_SECTION":"CBSS","STUDY_SECTION_NAME":"Cancer Biomarkers Study Section","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"5","TOTAL_COST":"326324","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8607498","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): Despite enormous efforts, no effective vaccine is currently available against HIV/AIDS. This is largely due to the virus's ability to evade neutralizing antibodies. The trimeric HIV envelope glycoprotein gp160 (HIV Env), which is exposed to the host immune response on the surface of the virion, effectively conceals epitopes from antibodies while maintaining its ability to promote viral entry. The few exposed antibody-binding sites are structurally unstable and sustain substantial sequence variability. Consequently, few broadly neutralizing antibodies have been identified. Here we will develop single molecule Fluorescence Resonance Energy Transfer (smFRET) imaging to monitor the conformational landscape of individual native Env molecules on the surface of an HIV virus. We will apply new enzymatic methods to introduce organic fluorophores into HIV Env at positions that don't interfere with infectivity. The placement of two dyes within one Env molecule will allow the application of smFRET to report conformational changes of the unliganded HIV Env from various angles. Following the characterization of the unliganded HIV Env, we will determine how its conformation dynamics change in response to receptor and antibody binding. Our approach will identify critical conformational states of HIV Env that should be targeted for vaccine development, reveal the molecular mechanism underlying immune evasion, and understand the potency of existing neutralizing antibodies.        ","ACTIVITY":"R21","ADMINISTERING_IC":"AI","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"01/03/2014","BUDGET_START":"02/01/2014","BUDGET_END":"01/31/2015","CFDA_CODE":"855","CORE_PROJECT_NUM":"R21AI100696","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"PA-11-261","FULL_PROJECT_NUM":"5R21AI100696-02","FUNDING_ICs":"NIAID:209613\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES","NIH_SPENDING_CATS":"","ORG_CITY":"NEW HAVEN","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"MICROBIOLOGY/IMMUN/VIROLOGY","ORG_DISTRICT":"03","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"YALE UNIVERSITY","ORG_STATE":"CT","ORG_ZIPCODE":"065103209","PHR":"PUBLIC HEALTH RELEVANCE: This application proposes the development of single-molecule Fluorescence Resonance Energy Transfer (smFRET) imaging to monitor the conformational landscape of individual trimeric HIV Env molecules on the surface of native HIV viruses. smFRET technology has the potential to elucidate the mechanism of immune evasion and antibody neutralization, and will aid in the rational design of vaccines directed against HIV Env.           ","PI_IDS":"7051811;","PI_NAMEs":"MOTHES, WALTHER H;","PROGRAM_OFFICER_NAME":"SHARMA, OPENDRA K.","PROJECT_START":"02/01/2013","PROJECT_END":"01/31/2015","PROJECT_TERMS":"Affect;AIDS/HIV problem;Antibodies;Antibody Binding Sites;Binding (Molecular Function);Communities;Coupled;Development;Dyes;Epitopes;Event;Exhibits;Fc Receptor;flexibility;Fluorescence;fluorophore;HIV;HIV Envelope Protein gp160;HIV-1;Image;Immune;Immune response;In Vitro;Individual;insight;interest;Kinetics;Label;Laboratories;Ligands;Methods;Modeling;Molecular;Molecular Conformation;Monitor;neutralizing antibody;novel;novel strategies;Peptides;Positioning Attribute;preference;Proteins;public health relevance;receptor;receptor binding;Relative (related person);Reporting;Research;research study;response;Sampling;single molecule;single-molecule FRET;Site;Structure;Surface;Techniques;Technology;Testing;tool;Vaccine Design;vaccine development;Vaccines;Validation;Viral;Virion;Virus;Work","PROJECT_TITLE":"Single molecule imaging of HIV Env","SERIAL_NUMBER":"100696","STUDY_SECTION":"VACC","STUDY_SECTION_NAME":"HIV/AIDS Vaccines Study Study Section","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"2","TOTAL_COST":"209613","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8697008","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): This four-year K01 award application is to provide intensive multi-disciplinary training and career development guidance for Dr. Yu-Hsiang Hsieh, PhD, an Assistant Professor in Emergency Medicine at the Johns Hopkins University, leading to his becoming an independent investigator. Under the guidance of world renowned, NIH-funded, experienced mentors, Drs. Richard Rothman, Joshua Epstein, and David Holtgrave, Dr. Hsieh will gain a set of complementary inter-disciplinary skills which will allow him to pursue research with a focus on devising and evaluating public health interventions for infectious diseases seen in acute care settings. The applicant will receive mentoring in: public health aspects of emergency medicine;infectious disease computational mathematical modeling;and cost-effectiveness analysis. The rationale for the work, evaluation of HIV screening strategies, comes from the fact that HIV incidence has remained unchanged in the U.S. over the past decade, with one in five infected remaining unaware of their serostatus. One of the cornerstones recently advanced by the CDC for controlling the epidemic is widespread screening in emergency department (ED) settings. While, increasing numbers of EDs across the U.S. have developed strategies to adapt HIV testing into routine practice, there have been no efforts to systematically address how effective ED-based HIV testing has been (relative to no ED-based testing), or, which of several testing strategies is optimal with regard to identifying the largest number of unrecognized cases, and decreasing community HIV transmission. A relatively new and innovative method of computational modeling, agent-based modeling (ABM), offers a potential means for handling the complexity of temporal dynamics of HIV epidemiology and human behaviors associated with availability of ED-based HIV testing services, and represents a promising approach for overcoming many of the shortcoming of conventional study designs. The goal of this research project is to: 1) derive a computational model for measuring the impact of ED HIV testing programs on the HIV epidemic in Baltimore, Maryland, using ABM methods;2) validate the derived ABM model;and 3) assess relative cost- effectiveness of ED HIV testing programs based on findings from the validated ABM model. The results of this study will provide new insights regarding current approaches to ED-based HIV testing programs and provide important cost-effectiveness data to inform local and national HIV testing strategies. The K01 award will provide Dr. Hsieh an intensive and directed mentored research experience in two new disciplines for him - infectious disease computational mathematical modeling, particularly ABM, and cost-effectiveness analysis. He will also receive needed training in the responsible conduct of research as well as longitudinal career guidance from an experience team. Together these experiences will equip him with the essential training and mentorship necessary to become an outstanding interdisciplinary independent public health investigator, who will build a research program focused on the study of infectious diseases in emergent, and acute care venues.         PROJECT NARRATIVE: Emergency department-based HIV testing programs in the United States have identified thousands of previously undiagnosed HIV-infected individuals since 2006, when the Centers of Disease Control and Prevention began to aggressively promote testing in this non-traditional health care venue. The applicant will pursue a period of intensive multi-disciplinary training in infectious disease mathematical modeling - particularly agent based modeling, and cost-effectiveness analysis, applying these methods to study public health screening in acute care settings. The rich research environment of Johns Hopkins University coupled with the nationally recognized team of expert mentors will lead to independent investigator status, and a career dedicated to research in the development and evaluation of public health intervention strategies which address a wide array of infectious diseases'threats seen in emergency and other acute episodic care settings.                ","ACTIVITY":"K01","ADMINISTERING_IC":"AI","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"07/11/2014","BUDGET_START":"08/01/2014","BUDGET_END":"07/31/2015","CFDA_CODE":"855","CORE_PROJECT_NUM":"K01AI100681","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"PA-11-190","FULL_PROJECT_NUM":"5K01AI100681-03","FUNDING_ICs":"NIAID:132182\\","FUNDING_MECHANISM":"Other Research Related","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES","NIH_SPENDING_CATS":"","ORG_CITY":"BALTIMORE","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"EMERGENCY MEDICINE","ORG_DISTRICT":"07","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"JOHNS HOPKINS UNIVERSITY","ORG_STATE":"MD","ORG_ZIPCODE":"212182608","PHR":" Project Narrative Emergency department-based HIV testing programs in the United States have identified thousands of previously undiagnosed HIV-infected individuals since 2006, when the Centers of Disease Control and Prevention began to aggressively promote testing in this non-traditional health care venue. The applicant will pursue a period of intensive multi-disciplinary training in infectious disease mathematical modeling - particularly agent based modeling, and cost-effectiveness analysis, applying these methods to study public health screening in acute care settings. The rich research environment of Johns Hopkins University coupled with the nationally recognized team of expert mentors will lead to independent investigator status, and a career dedicated to research in the development and evaluation of public health intervention strategies which address a wide array of infectious diseases'threats seen in emergency and other acute episodic care settings.","PI_IDS":"8633321;","PI_NAMEs":"HSIEH, YU-HSIANG;","PROGRAM_OFFICER_NAME":"MCKAIG, ROSEMARY G.","PROJECT_START":"08/15/2012","PROJECT_END":"07/31/2016","PROJECT_TERMS":"Accident and Emergency department;Acute;Address;Affect;AIDS prevention;AIDS/HIV problem;Area;Baltimore;base;Behavior;care seeking;career;career development;Caring;Centers for Disease Control and Prevention (U.S.);Characteristics;Cities;Clinic;Clinical Trials;Communicable Diseases;Communities;Complex;Computer Simulation;Computer software;Computing Methodologies;cost;cost effective;cost effectiveness;Cost Effectiveness Analysis;Coupled;Data;demographics;design;Development;Diagnostic tests;Discipline;disorder prevention;Doctor of Philosophy;Ear structure;Effectiveness;Emergency Medicine;Emergency Situation;Environment;Epidemic;Epidemiologic Studies;Epidemiology;Evaluation;experience;Exposure to;Funding;Goals;Health Care Seeking Behavior;Healthcare;Heterogeneity;High Prevalence;high risk behavior;HIV;Human;Human immunodeficiency virus test;Incidence;Individual;Infection;Infection Control;Influenza A Virus, H1N1 Subtype;injection drug use;inner city;innovation;insight;Intervention;Lead;Maryland;mathematical model;Measures;Medical;Mentored Research Scientist Development Award;Mentors;Mentorship;methicillin resistant Staphylococcus aureus (organism);Methods;Mission;Modeling;Movement;novel strategies;Observational Study;Outcomes Research;outreach;Play;Population;Prevention strategy;professor;programs;prospective;public health medicine (field);Recording of previous events;Relative (related person);Research;Research Design;Research Personnel;Research Project Grants;Research Scientist Award;response;responsible research conduct;routine practice;screening;Seroepidemiologic Studies;Services;Sex Behavior;Simulate;skills;Smallpox;social;Societies;Structure;Techniques;Testing;Time;Training;transmission process;United States;United States National Institutes of Health;Universities;Validation;Work","PROJECT_TITLE":"Cost-Effectiveness of ED HIV Testing Program Agent-Based Modeling Approach","SERIAL_NUMBER":"100681","STUDY_SECTION":"AIDS","STUDY_SECTION_NAME":"Acquired Immunodeficiency Syndrome Research Review Committee","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"3","TOTAL_COST":"132182","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8725943","ABSTRACT_TEXT":"Antigen presenting cells (APCs) are critical for the induction of graft-versus-host / leukemia responses  after allogeneic bone marrow transplantation (BMT). Therefore agents that target dendritic cells (DCs),  the most potent APCs, might have therapeutic potential in graft-versus-host disease (GVHD). Histone  deacetylase inhibitors (HDACi) are novel anti-tumor agents that appear to be well tolerated in human  clinical trials. However their immuno-modulatory effects have heretofore been largely unrecognized.  Preliminary data generated and published by us demonstrate that HDACi regulate experimental acute  GVHD, in part, through induction of the immuno-regulatory enzyme indoleamine 2, 3 dioxygenase (IDO)  in host DCs. These exciting pre-clinical data formed the rationale for the development of a proof in  principle clinical trial that will test the effects of HDACi, vorinostat, in prevention of acute GVHD.  Preliminary data also demonstrate that acetylation of non-histone protein, STAT-3, in DCs is critical for  the induction of IDO by the HDACi. The specificity of the approach and the precise molecular  mechanisms are not known. This proposal flows from our exciting published and unpublished  observations generated from murine models and primary healthy human cells. We will test the central  hypothesis that acetylation of non-histone protein, STAT-3, by HDACi is critical for suppression of DCs  and the negative regulation of experimental GVHD. The Specific Aims are:  1. To determine the specific HDAC enzyme critical for acetylation of STAT-3 and regulation of DC  function by the HDACi  2. To elucidate the critical role of STAT-3 in regulation of DCs and GVHD by HDACi  3. To analyze the cellular markers of HDAC inhibition after vorinostat (an HDACi) administration  following reduced intensity conditioning (RIC) allogeneic BMT","ACTIVITY":"P01","ADMINISTERING_IC":"CA","APPLICATION_TYPE":"7","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"09/19/2014","BUDGET_START":"09/01/2014","BUDGET_END":"08/31/2015","CFDA_CODE":"","CORE_PROJECT_NUM":"P01CA039542","ED_INST_TYPE":"","FOA_NUMBER":"PAR-09-025","FULL_PROJECT_NUM":"7P01CA039542-27","FUNDING_ICs":"NCI:705818\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL CANCER INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"NEW YORK","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"13","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI","ORG_STATE":"NY","ORG_ZIPCODE":"100296574","PHR":"Allogeneic hematopoietic stem cell transplantation is a potentially curative therapy for many malignant  diseases whose applicability has been impeded by the development of its most serious complication,  GVHD. Strategies that mitigate GVHD will allow for better harnessing of this effective therapeutic modality  to treat many patients with hematological cancers.","PI_IDS":"6564538;","PI_NAMEs":"REDDY, PAVAN;","PROGRAM_OFFICER_NAME":"","PROJECT_START":"","PROJECT_END":"","PROJECT_TERMS":"Acetylation;Acute Graft Versus Host Disease;Adverse effects;Allogeneic Bone Marrow Transplantation;Allogenic;Antigen-Presenting Cells;antitumor agent;bench to bedside;Biology;Bone Marrow Transplantation;Cell model;Cell physiology;Cells;Cellular biology;Clinical;Clinical Data;Clinical Trials;Complication;conditioning;Data;Dendritic Cells;Development;Dioxygenases;Disease;Enzymes;Epigenetic Process;Graft-vs-Host Disease;Hematopoietic Stem Cell Transplantation;Histone Acetylation;Histone Deacetylase Inhibitor;Histones;Human;Human Volunteers;Immune response;indoleamine;Inflammatory Response;inhibitor/antagonist;insight;Lead;leukemia;Lysine;Malignant - descriptor;Malignant Neoplasms;meetings;Modality;Modeling;Modification;Molecular;Mus;novel;Pathway interactions;Patients;Peripheral Blood Mononuclear Cell;Play;pre-clinical;prevent;Prevention;Process;Proteins;Publishing;Regulation;response;Role;Sampling;Specificity;STAT protein;Testing;Therapeutic;translational study;Translations;Vorinostat","PROJECT_TITLE":"HDAC Inhibition to prevent GVHD","SERIAL_NUMBER":"39542","STUDY_SECTION":"ZCA1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"5816","SUFFIX":"","SUPPORT_YEAR":"27","TOTAL_COST":"","TOTAL_COST_SUB_PROJECT":"705818"}
{"APPLICATION_ID":"8574224","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): Major Depressive Disorder (MDD) is one of the most prevalent mental disorders, and is associated with significant mortality, morbidity, and economic costs. The Stony Brook Temperament Study is an ongoing longitudinal study that seeks to identify early behavioral precursors/risk factors for depression and understand the neurobiological and psychosocial processes through which these early manifestations develop into MDD. This information about risk pathways and processes should contribute to understanding when and how to intervene in order to prevent the disorder and limit its progression. The study initially assessed a large community sample of 3-year old children, followed them up at age 6, and is currently evaluating them in middle childhood (age 9). This competing renewal application seeks to extend the study into adolescence, the beginning of the peak risk period for onset of MDD. Specifically, the application proposes to map pathways from laboratory observations of low positive emotionality and high negative emotionality at age 3 to neural indices of emotional and social information processing, hypothalamic-pituitary-adrenal axis dysregulation, and emerging depressive and anxiety symptoms in early- (age 12) and mid- (age 15) adolescence. In addition, it seeks to understand the role of pubertal development and life stress in influencing these trajectories, and to capture the early portion of the expected sure in first-onset MDD that begins at puberty and continues through early adulthood.        ","ACTIVITY":"R01","ADMINISTERING_IC":"MH","APPLICATION_TYPE":"2","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"03/21/2014","BUDGET_START":"05/01/2014","BUDGET_END":"04/30/2015","CFDA_CODE":"242","CORE_PROJECT_NUM":"R01MH069942","ED_INST_TYPE":"SCHOOLS OF ARTS AND SCIENCES","FOA_NUMBER":"PA-11-260","FULL_PROJECT_NUM":"2R01MH069942-10","FUNDING_ICs":"NIMH:783743\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF MENTAL HEALTH","NIH_SPENDING_CATS":"","ORG_CITY":"STONY BROOK","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"PSYCHOLOGY","ORG_DISTRICT":"01","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"STATE UNIVERSITY NEW YORK STONY BROOK","ORG_STATE":"NY","ORG_ZIPCODE":"117940001","PHR":"PUBLIC HEALTH RELEVANCE: The depressive disorders are highly prevalent and associated with significant mortality, morbidity, and economic costs. This project seeks to identify early behavioral precursors/risk factors for major depressive disorder and understand the neurobiological and psychosocial processes through which these early manifestations develop into clinically significant psychopathology. This will contribute to understanding when and how to intervene in order to prevent the disorder and/or its progression.            ","PI_IDS":"1897962;","PI_NAMEs":"KLEIN, DANIEL N;","PROGRAM_OFFICER_NAME":"GARRIOCK, HOLLY A.","PROJECT_START":"12/01/2003","PROJECT_END":"04/30/2019","PROJECT_TERMS":"3 year old;Accounting;Adolescence;adolescent-onset depression;Age;age effect;Anxiety;Aversive Stimulus;base;Behavioral;Behavioral inhibition;Child;Childhood;clinically significant;Communities;Depressive disorder;depressive symptoms;Development;Developmental Process;Diagnosis;Disease;Distal;Early identification;Early Intervention;economic cost;emerging adult;Emotional;Event-Related Potentials;Exhibits;Family;Feedback;Female;Foundations;Gender;Hormones;Hydrocortisone;hypothalamic-pituitary-adrenal axis;indexing;information processing;Knowledge;Laboratories;Life Stress;Link;Longevity;Longitudinal Studies;Major Depressive Disorder;Maps;Measures;Mediating;Mental Depression;Mental disorders;Morbidity - disease rate;Mortality Vital Statistics;National Institute of Mental Health (U.S.);Neurobiology;Outcome;Parenting behavior;Pathway interactions;peer;prevent;Preventive Intervention;Process;Process Measure;Psychopathology;psychosocial;Puberty;public health relevance;relating to nervous system;Research Domain Criteria;reward processing;Rewards;Risk;Risk Factors;Role;Sampling;social;Stimulus;stimulus processing;Strategic Planning;Stress;Symptoms;System;Temperament;Time","PROJECT_TITLE":"Temperamental emotionality in preschoolers and risk for depression","SERIAL_NUMBER":"69942","STUDY_SECTION":"CPDD","STUDY_SECTION_NAME":"Child Psychopathology and Developmental Disabilities Study Section","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"10","TOTAL_COST":"783743","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8716060","ABSTRACT_TEXT":"The goal ofthe Developmental Research Project Program ofthe Maine INBRE (ME-INBRE) is to support the  research and career development of exceptional INBRE-affiliated faculty who are engaged in biomedical  research and research training focused on the unifying theme of comparative functional genomics. Faculty  will be selected on a competitive basis, via review by the ME-INBRE External Advisory Committee (EAC),  from applicants who respond to Funding Opportunity Announcements (FOA) distributed within the MEINBRE  network. This program has two specific aims. The first is to provide research funding and  mentorship for ME-INBRE Investigators. Selected Investigators will be expected to devote 50% effort to their  proposed research project, actively engage mentors and implement individualized development plans,  mentor students and/or postdoctoral fellows, submit quarterly progress reports, publish in peer-reviewed  journals, present at national and/or international meetings, and participate in INBRE-sponsored workshops.  Investigators at research institutions will also be expected to apply for independent ROI-level research  funding by the end of the second year of funding. Investigator appointments will be renewed annually for up  to 5 years contingent on review of progress by the ME-INBRE Principal Investigator (PI), Program  Coordinator (PC), and EAC. The second aim of the program is to provide more opportunities for faculty-led  research and training on site at primarily undergraduate (partner) institutions. This will be accomplished by  granting Research Training Faculty awards to selected faculty who have demonstrated an ability to  effectively engage students in cutting-edge research related to the theme of this INBRE. Research Training  Faculty will devote 15-25% effort to their project, actively engage mentors and implement individualized  development plans, engage students in research, submit quarterly progress reports, present at regional  and/or national meetings, submit the results for publication in peer-reviewed journals, and participate in  INBRE-sponsored workshops. Research Training Faculty will build biomedical research capacity by  providing additional high-level opportunities for student research and training. For both aims, emphasis will  be placed on mentorship (both of faculty and their students and trainees) and evaluation. Successful  implementation of the two aims of the Developmental Research Projects Program will be facilitated by  regular internal formative evaluations and measured by a final summative evaluation carried out by the PI,  PC, EAC, Evaluation Coordinator, an independent evaluation consultant, and an AAAS review panel.","ACTIVITY":"P20","ADMINISTERING_IC":"GM","APPLICATION_TYPE":"2","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"05/27/2014","BUDGET_START":"06/01/2014","BUDGET_END":"04/30/2015","CFDA_CODE":"","CORE_PROJECT_NUM":"P20GM103423","ED_INST_TYPE":"","FOA_NUMBER":"PAR-12-205","FULL_PROJECT_NUM":"2P20GM103423-14","FUNDING_ICs":"NIGMS:996458\\","FUNDING_MECHANISM":"Research Centers","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES","NIH_SPENDING_CATS":"","ORG_CITY":"SALSBURY COVE","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"02","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"MOUNT DESERT ISLAND BIOLOGICAL LAB","ORG_STATE":"ME","ORG_ZIPCODE":"046720035","PHR":"Improving public health requires advances in biomedical research and an informed, skilled workforce able to  leverage the information being produced by high-throughput genomics technology at a rapidly accelerating  rate. The Developmental Research Project Program ofthe Maine-INBRE will fill this need both by increasing  the excellence of ongoing genomics-oriented biomedical research across the state of Maine, and by  expanding opportunities for the high-level training needed to support growth of the relevant workforce.","PI_IDS":"7709147;","PI_NAMEs":"HAND, PATRICIA H.;","PROGRAM_OFFICER_NAME":"","PROJECT_START":"","PROJECT_END":"","PROJECT_TERMS":"Advisory Committees;American Association for the Advancement of Science;Appointment;Award;base;Biomedical Research;career development;comparative;Development;Development Plans;Educational Status;Educational workshop;Evaluation;Faculty;functional genomics;Funding;Funding Opportunities;Genomics;Goals;Grant;Growth;improved;Institution;International;Journals;Maine;Measures;meetings;Mentors;Mentorship;Peer Review;Postdoctoral Fellow;Principal Investigator;Program Research Project Grants;programs;Progress Reports;public health medicine (field);Publications;Publishing;Research;research and development;Research Personnel;Research Project Grants;Research Training;Site;Students;Technology","PROJECT_TITLE":"DEVELOPMENTAL RESEARCH PROJECT PROGRAM","SERIAL_NUMBER":"103423","STUDY_SECTION":"ZGM1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"7060","SUFFIX":"","SUPPORT_YEAR":"14","TOTAL_COST":"","TOTAL_COST_SUB_PROJECT":"996458"}
{"APPLICATION_ID":"8692071","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): This project will develop a new approach to treat an aggressive and deadly form of metastatic breast cancer known as meningeal metastases, or metastases to the lining covering the brain. We propose to investigate an effective, long lasting, and targeted therapy with oncolytic replication conditional herpes simplex virus 1 (HSV-1) that will potentially have a large impact on the treatment of meningeal metastases by reducing toxicity, promoting effective treatment outcome, and most significantly -prolonging life expectancy.  Meningeal metastasis is a deadly complication of breast cancer affecting approximately 5% of patients. At present, there is no effective therapy for meningeal metastases, and the median survival of the treated patients is about 3 months. Published data suggest that the incidence of this disease increases, probably due to the longer survival of patients with systemic cancer. The need for new therapeutic interventions is urgent.  The replication conditional herpes simplex type-1 (HSV-1) has been genetically engineered to replicate preferentially in cancer cells utilizing their enhanced mitotic activity. As such replicaion in cancer cells will kill these cells while leaving the normal tissue unharmed. This novel treatment will be investigated in a mouse model of meningeal metastases that has been fully characterized with molecular imaging with MRI over successive time points. The potential therapeutic effect of HSV-1 oncolysis on meningeal metastases will be investigated with molecular imaging and in vitro tissue analyses sequentially over time. Virus replication in the meningeal metastases will be determined by molecular imaging with positron emission tomography (PET) using FHBG as the substrate for the thymidine kinase enzyme specific for the virus. The therapeutic effect of oncolytic HSV-1 on meningeal metastases will be determined by molecular imaging with Gd enhanced MRI. If a therapeutic effect is achieved, the impact on therapy and patient survival will be huge and will be of direct clinical significance.        ","ACTIVITY":"R21","ADMINISTERING_IC":"CA","APPLICATION_TYPE":"1","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"02/19/2014","BUDGET_START":"04/01/2014","BUDGET_END":"03/31/2015","CFDA_CODE":"395","CORE_PROJECT_NUM":"R21CA186054","ED_INST_TYPE":"","FOA_NUMBER":"PAR-13-146","FULL_PROJECT_NUM":"1R21CA186054-01","FUNDING_ICs":"NCI:226938\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL CANCER INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"BOSTON","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"07","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"MASSACHUSETTS GENERAL HOSPITAL","ORG_STATE":"MA","ORG_ZIPCODE":"021997603","PHR":"PUBLIC HEALTH RELEVANCE: Meningeal metastasis is a devastating and often fatal complication of breast cancer that affects 5-8% of patients. It results when circulating cancer cells seed in the meninges. Their subsequent growth causes severe neurological complications involving the cranial nerves, cerebrum and spinal cord, limiting life expectancy to less than 4 months. Current treatment is largely palliative. Aggressive multimodal therapies including intrathecal chemotherapy are often ineffective. Given this clear unmet clinical need, I am proposing to assess surgically delivered targeted replication conditional oncolytic herpes simplex 1 (HSV-1) therapy as a novel platform to treat meningeal metastases from breast cancer. These modified viruses replicate in and kill tumor cells while sparing normal adjacent tissue.            ","PI_IDS":"8016561;","PI_NAMEs":"KURUPPU, KUMUDU DARSHINI;","PROGRAM_OFFICER_NAME":"WELCH, ANTHONY R","PROJECT_START":"04/01/2014","PROJECT_END":"03/31/2016","PROJECT_TERMS":"Affect;Bioluminescence;Blood;Blood - brain barrier anatomy;Brain;Brain region;cancer cell;cell killing;Cerebrum;chemotherapy;circulating cancer cell;Clinical;clinically significant;Combined Modality Therapy;Complication;Cranial Nerves;Data;Disease;effective therapy;Enzymes;Future;Genetic Engineering;Growth;Herpes Simplex Infections;Herpesvirus 1, Human;Histology;In Vitro;in vivo;Incidence;Intrathecal Chemotherapy;Killings;Left;Life Expectancy;Magnetic Resonance Imaging;malignant breast neoplasm;Malignant Neoplasms;Meninges;Metastatic Neoplasm to the Leptomeninges;Mitotic Activity;molecular imaging;mouse model;Neoplasm Metastasis;neoplastic cell;Neurologic;Normal tissue morphology;novel;novel strategies;novel therapeutic intervention;oncolysis;Oncolytic;palliative;Patients;Pilot Projects;Plaque Assay;Positron-Emission Tomography;public health relevance;Publishing;response;Seeds;Side;Spinal Cord;Structure;Therapeutic;Therapeutic Effect;Thymidine Kinase;Time;Tissues;Toxic effect;Translations;Treatment outcome;tumor;Virion;Virus;Virus Replication","PROJECT_TITLE":"Novel oncolytic HSV-1 therapy for breast cancer meningeal metastases","SERIAL_NUMBER":"186054","STUDY_SECTION":"ZCA1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"1","TOTAL_COST":"226938","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8644130","ABSTRACT_TEXT":"   DESCRIPTION (provided by applicant): Molecular mechanisms underlying blood development and disorders are of great interest and importance from the perspective of understanding normal function and leukemias. Drosophila has long served as a genetic model for many developmental processes, but its usefulness as a hematopoietic model has only recently been appreciated. The mechanisms that maintain blood stem cells in Drosophila show remarkable conservation in strategy of development and function with mammalian systems. The proposed work intends to determine the molecular pathways that maintain stem cell homeostasis. Also proposed is the role of systemic signals and nutrient deprivation on myeloid cell development. These are developmentally and medically relevant problems for which model systems amenable to genetic screens are essential to develop. The proposal has four specific aims. In Aim 1, a homeostatic model by which blood precursors are maintained not only by a signal from a niche, but also from the cells that have started differentiating will be developed. In Aim 2, the involvement of the transcription factor STAT in the maintenance of stem cell fate in Drosophila will be investigated. In Aim 3, the role of extracellular matrix components that control the integrity of stem cells will be studied. In the final aim, signals arising from the brain that control blood stem cell maintenance in Drosophila will be investigated and their role in starvation induced stem cell loss studied.        ","ACTIVITY":"R01","ADMINISTERING_IC":"HL","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"03/15/2014","BUDGET_START":"04/01/2014","BUDGET_END":"03/31/2015","CFDA_CODE":"837","CORE_PROJECT_NUM":"R01HL067395","ED_INST_TYPE":"SCHOOLS OF ARTS AND SCIENCES","FOA_NUMBER":"PA-10-067","FULL_PROJECT_NUM":"5R01HL067395-13","FUNDING_ICs":"NHLBI:377300\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL HEART, LUNG, AND BLOOD INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"LOS ANGELES","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"BIOCHEMISTRY","ORG_DISTRICT":"33","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF CALIFORNIA LOS ANGELES","ORG_STATE":"CA","ORG_ZIPCODE":"900952000","PHR":" The genetic basis of blood development and disorders are extremely important to understand in order to make progress on understanding immune challenges and leukemias. The fruit fly, Drosophila is a model organism in which such studies can be achieved with great predictive power for the human condition. This proposal seeks to understand the molecular mechanisms by which blood stem cells are maintained, and also how these cells respond to stresses that result from starvation.         ","PI_IDS":"1965866;","PI_NAMEs":"BANERJEE, UTPAL;","PROGRAM_OFFICER_NAME":"THOMAS, JOHN ","PROJECT_START":"05/10/2001","PROJECT_END":"03/31/2015","PROJECT_TERMS":"Adenosine;adenosine deaminase;Animal Model;base;Biological Assay;Biological Models;Blood;Brain;Cell Count;Cell Culture Techniques;Cell Maintenance;Cells;Characteristics;Collagen Type IV;Cyclic AMP-Dependent Protein Kinases;Data;deprivation;detection of nutrient;Development;Developmental Process;Disease;Dissection;Drops;Drosophila genus;Enzymes;Equilibrium;Erinaceidae;extracellular;Extracellular Matrix;factor A;Feeds;Funding;gain of function;Generations;Genetic;genetic analysis;Genetic Models;Genetic Screening;Grant;Growth Factor;Hematopoiesis;Hematopoietic;Hematopoietic stem cells;Homeostasis;Human;Immune;Immunity;Inosine;Insulin;Insulin Receptor;insulin signaling;Integrins;interest;Laboratories;Laminin;leukemia;Ligands;Lobe;lymph nodes;Maintenance;Mediating;mind control;Modeling;Molecular;Monitor;Myelogenous;Myeloid Cells;Neuroendocrine Cell;Nutrient;Pathway interactions;perlecan;Platelet-Derived Growth Factor;Play;Process;Proteins;receptor;Receptor Protein-Tyrosine Kinases;research study;response;Role;Signal Pathway;Signal Transduction;Site;small molecule;smoothened signaling pathway;Starvation;stem cell fate;Stem cells;Stress;System;Testing;transcription factor;Vascular Endothelial Growth Factors;Work","PROJECT_TITLE":"Genetic Dissection of Drosophila Hematopoiesis","SERIAL_NUMBER":"67395","STUDY_SECTION":"DEV1","STUDY_SECTION_NAME":"Development - 1 Study Section","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"13","TOTAL_COST":"377300","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8702828","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): The objective of this grant application is to develop a clinical tool for real-time assessment of irradiated brain tissue during neurosurgical resection or stereotaxic biopsy in patients with brain tumor recurrence. Primary and many metastatic brain tumors recur after radiation therapy (RT). However, identifying cancer recurrence is complicated by the development of radiation necrosis. It is important to rapidly distinguish radiation-injury from recurrent cancer during interventional neurosurgical procedures. Radiation necrosis and cancer are managed very differently. To address this problem, we propose development of a label-free, non-ionizing tissue assessment technique, i.e. Multispectral Scanning -Time Resolved Fluorescence Spectroscopy (MS-TRFS), which facilitates rapid in vivo evaluation of the biochemical and functional characteristics of brain tissue. The proposed technique can multispectrally evaluate the fluorescent decay of multiple cellular metabolites (NAD(P)H and other fluorescent constituents such as proteins and lipids) and is well suited to assess the biochemical features associated with radiation necrosis, malignant, and normal tissue. In this R21 application, we will test the ability of MS-TRFS to detect brain alterations associated with radiation necrosis. Two specific aims will be addressed. The first aim is designed to (i) provide a systematic evaluation of time-resolved fluorescence features associated with tissue radiation necrosis and (ii) support the identification of biochemical components contributing to unique autofluorescence signatures that can act as diagnostic markers of radiation necrosis. The second aim is focused on a proof-of-concept study in human patients designed to demonstrate whether a clinically compatible MS-TRFS device can be used for rapid diagnosis of radiation necrosis in the brain. If MS-TRFS proves useful in reliably distinguishing radiation necrosis from other brain tissue types in these pre-clinical and clinical studies, we anticipate further development of a specialized clinical MS-TRFS-based tool to aid in brain tumor surgical resection in the presence of radiation necrosis or during brain tissue stereotaxic biopsy. This has the potential to improve the clinical management of radiation necrosis and overall patient outcome. In addition, the small fiber optic probe size required enables further development of MS-TRFS as a pre-clinical research tool that can play a role in the optimization of RT. We envision that a MS-TRFS probe introduced in a rodent model into a tumor region by neurointerventional technology could also be used to monitor RT dosimetry and local tissue response.        ","ACTIVITY":"R21","ADMINISTERING_IC":"CA","APPLICATION_TYPE":"1","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"08/27/2014","BUDGET_START":"09/01/2014","BUDGET_END":"08/31/2015","CFDA_CODE":"394","CORE_PROJECT_NUM":"R21CA178578","ED_INST_TYPE":"BIOMED ENGR/COL ENGR/ENGR STA","FOA_NUMBER":"PA-12-284","FULL_PROJECT_NUM":"1R21CA178578-01A1","FUNDING_ICs":"NCI:196906\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL CANCER INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"DAVIS","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"BIOMEDICAL ENGINEERING","ORG_DISTRICT":"03","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF CALIFORNIA AT DAVIS","ORG_STATE":"CA","ORG_ZIPCODE":"956186153","PHR":"PUBLIC HEALTH RELEVANCE: Difficulties in differentiating tumor recurrence from radiation injury complicates treatment of post-radiation therapy patients with brain tumor recurrence. There are no effective tools for real-time assessment of irradiated tissue during neurosurgical interventions or stereotaxic biopsies. We propose development of a label-free, non- ionizing tissue assessment technique, i.e. Multispectral Scanning -Time Resolved Fluorescence Spectroscopy (MS-TRFS), which facilitates rapid in vivo evaluation of the biochemical and functional characteristics of brain tissue. The MS-TRFS probe will allow neurosurgeons to rapidly survey the tumor/necrotic mass in multiple areas, quickly determine if specific areas are consistent with radiation necrosis or tumor, assess tumor borders, and avoid the destructive and potentially damaging removal of tissue required for conventional histopathology. The MS-TRFS probe can also assist stereotaxic brain biopsy by assessing the nature of the tissue before tissue removal. The proposed technology also has an important role as a pre-clinical platform for assessing the response to experimental therapies in animal models of radiation necrosis.                ","PI_IDS":"6647839;","PI_NAMEs":"MARCU, LAURA;","PROGRAM_OFFICER_NAME":"BAKER, HOUSTON ","PROJECT_START":"09/01/2014","PROJECT_END":"08/31/2016","PROJECT_TERMS":"Address;Adult;Aftercare;Algorithms;Animal Model;Applications Grants;Area;base;Biochemical;Biochemical Markers;Biopsy;Brain;Brain Neoplasms;brain surgery;brain tissue;brain tumor resection;Caliber;cancer recurrence;Characteristics;Classification;Clinical;Clinical Management;Clinical Research;clinically relevant;Cranial Irradiation;Craniotomy;Data;design;Detection;Development;Devices;Diagnosis;Diagnostic;dosimetry;Evaluation;Excision;Fiber Optics;Fluorescence;Fluorescence Spectroscopy;Future;Glioma;Histocompatibility Testing;Histocytochemistry;Histology;Histopathology;Human;hypodermic needle;Immunohistochemistry;improved;in vivo;Injury;Intervention;Investigational Therapies;Label;Laboratories;Lipids;Malignant - descriptor;Malignant Neoplasms;Metastatic/Recurrent;mind control;miniaturize;Modeling;Monitor;Nature;Necrosis;Needle biopsy procedure;Neurosurgeon;Neurosurgical Procedures;non-invasive imaging;Nonionizing Radiation;Normal tissue morphology;novel;Operative Surgical Procedures;Optics;Outcome;Patients;Play;pre-clinical;Pre-Clinical Model;pre-clinical research;Procedures;Proteins;prototype;public health relevance;Radiation;Radiation Injuries;Radiation necrosis;Radiation therapy;rapid diagnosis;Rattus;Recurrence;Recurrent Malignant Neoplasm;Recurrent tumor;response;Risk;Rodent;Rodent Model;Role;Sampling;Sampling Errors;Scanning;Specificity;Surveys;System;Techniques;Technology;technology development;Testing;Time;Tissues;tool;tumor;two-dimensional;Work","PROJECT_TITLE":"Fluorescence lifetime technique for detection of radiation necrosis vs gliom","SERIAL_NUMBER":"178578","STUDY_SECTION":"ZRG1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"A1","SUPPORT_YEAR":"1","TOTAL_COST":"196906","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8823186","ABSTRACT_TEXT":"2.1. SCIENTIFIC RATIONALE. Wide global variation in age standardized rates of colorectal cancer (CRC) of 1.2 to 45.0/100,000 largely reflect the impact of dietary and lifestyle factors in the etiology of the disease.''The influence of the environment on CRC is evidenced by the change in CRC rates among 1st- and 2nd-generation immigrants to that of the host country, regardless of genetic background. Dietary and other lifestyle effects on the gut microbiome have long been postulated to explain these population differences in CRC rates. With recent advances in sequencing technology, it is now clear that diet and lifestyle (e.g., smoking, obesity, physical activity) significantly influence the composition of the gut microflora[2] with findings from experimental models and humans providing solid evidence for link between gut microbiota and CRC.[3-6] These findings has revitalized interest in the contribution of gut microbiota to CRC with particular interest in how the gut microbiome disturbs normal tissue homeostasis to enhance susceptibility to CRC as prevention targets.[3-6]    A long-standing interest of the UACC group is the role of bile acids (BA) and CRC. BAs, particularly the secondary BAs, are strongly suspect in CRC etiology.[7-8] Secondary BAs are produced by intestinal bacteria to salvage BAs that escape transport in the distal ileum.[9] These excess BAs act as substrates for intestinal bacterial dependent deconjugation of the hydroxy groups at C-3, C-7 and C-12 and 7alpha/Beta-dehydroxylation.[9-10] These bacteria-dependent processes give rise to suspected carcinogens: deoxycholic acid (DCA) and lithocholic acid (LCA). Our preliminary data suggest that the composition of the gut flora influences the composition of fecal BAs;which we postulate influences individual risk of neoplasia in the colorectum.    In this proposal our primary hypothesis is that lifestyle, diet, and health status impact the functional component of the gut microbiome and that these factors collectively influence the colonic BA composition as a risk factor for CRC. Our secondary hypothesis is that the effect(s) of shared environmental factors on the functional component of the gut microbiome that leads to production of pro-tumorigenic fecal BAs is largely independent of race/ethnicity and reflects the sharing of environmental factors.    In our studies of colorectal adenoma (CRA) (i.e., the premalignant precursor for CRC), minority populations are grossly underrepresented. As such, a major limitation of our studies is our inability to generalize findings on CRC risk factors and intervention targets to populations relevant to Arizona including Native Americans (NA). For NAs, a major challenge is the relatively small size of the population. The low population density, relative to non-Hispanic White (NHW), is a major factor in their underrepresentation. One strategy to assess the relative importance of our findings from NHW to the NA community is to test whether relationships between diet and the gut microbiome on fecal BA composition observed in NHW are similar in NA;particularly any found to be strongly associated with the risk of CRC. As part of our planned efforts described in the specific aims below, we will also initiate and effort to test if relationships observed between BAs (pro or anti-tumorigenic) and the gut microbiota and CRA identified in Aims 1 and 2 in NHWs are also present in NA populations.    2.2. SCIENTIFIC AIMS  S.1 In cross-section (baseline only), determine the association between the gut microbiome and the fecal BA composition in 735 participants of a Phase III trial to prevent CRA, considering the effects of age, sex, diet, and other factors (e.g., smoking, obesity, race/ethnicity and diabetes).    S.2 Test if baseline gut microbiome composition is associated with development of CRA and whether any association between the gut microbiome and CRA is dependent on baseline fecal BA composition, considering the intervention with ursodeoxycholic acid (UDCA).    S.3 Characterize differences in the gut microbiome and BA compositions in rural and urban dwelling Navajo and relate the findings to those observed in the study of NHWs at risk of CRC. The training component of this aim is for mentee Dr Yellowhair [mentored by Dr Thompson] to lead an effort to describe the gut microbiome and BA composition and levels in Navajo, considering urbanization, age, sex, and lifestyle (diet and exercise).    2.3 IMPACT. Identification of the factors (BAs, gut microbiome) that mediate the role of the environment in CRC will allow us to better target and modify the physiological factors that underlie the elevated CRC risk that occurs with modern diet and lifestyle factors. Further, demonstration of shared physiological consequences across NHW and NA populations would vastly enhance our ability to extrapolate findings from one population to another.","ACTIVITY":"U54","ADMINISTERING_IC":"CA","APPLICATION_TYPE":"2","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"09/24/2014","BUDGET_START":"09/19/2014","BUDGET_END":"08/31/2015","CFDA_CODE":"","CORE_PROJECT_NUM":"U54CA143925","ED_INST_TYPE":"","FOA_NUMBER":"PAR-12-055","FULL_PROJECT_NUM":"2U54CA143925-06","FUNDING_ICs":"NCI:92897\\","FUNDING_MECHANISM":"Research Centers","FY":"2014","IC_NAME":"NATIONAL CANCER INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"FLAGSTAFF","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"01","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"NORTHERN ARIZONA UNIVERSITY","ORG_STATE":"AZ","ORG_ZIPCODE":"860114130","PHR":"","PI_IDS":"8324555;10108300 (contact);8082689;11506807;","PI_NAMEs":"INGRAM, JANI CHERI;PEARSON, TALIMA ROSS (contact);STEARNS, DIANE M;TRUJILLO, OCTAVIANA V;","PROGRAM_OFFICER_NAME":"","PROJECT_START":"09/29/2009","PROJECT_END":"08/31/2019","PROJECT_TERMS":"Age;age effect;Arizona;Bacteria;Bile Acids;Cancer Etiology;cancer prevention;cancer risk;Carcinogens;Colorectal Adenoma;Colorectal Cancer;Communities;Country;Data;dehydroxylation;Deoxycholic Acid;Development;Diabetes Mellitus;Diet;diet and exercise;Dietary Factors;Disease;Distal;Environment;Environmental Risk Factor;Ethnicity aspects;Etiology;Experimental Models;Generations;Genetic;gut microbiota;gut microflora;Health Status;Homeostasis;Human;ileum;Immigrant;Individual;interest;Intervention;Intestines;Lead;Life Style;lifestyle factors;Link;Lithocholic Acid;Mediating;Mentors;Microbe;microbiome;Minority;Native Americans;Navaho;Neoplasms;Normal tissue morphology;Not Hispanic or Latino;Obesity;Participant;Phase III Clinical Trials;Physical activity;Physiological;Population;Population Density;Population Sizes;Predisposition;Premalignant;prevent;Prevention;Process;Production;Race;Relative (related person);Risk;Risk Factors;Role;Rural;sex;Smoking;Solid;Technology;Testing;Training;tumorigenic;Urbanization;Ursodeoxycholic Acid;Variant","PROJECT_TITLE":"MICROBES, BILE ACIDS AND COLORECTAL CANCER","SERIAL_NUMBER":"143925","STUDY_SECTION":"ZCA1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"6754","SUFFIX":"","SUPPORT_YEAR":"6","TOTAL_COST":"","TOTAL_COST_SUB_PROJECT":"92897"}
{"APPLICATION_ID":"8946388","ABSTRACT_TEXT":"Mast cells play a pivotal role in the pathogenesis of allergic inflammation. These reactions are generally initiated by antigen-dependent aggregation of the high affinity IgE receptor (Fc-epsilon-RI) expressed on the cell surface and subsequent release of pro-inflammatory mediators. Ligands for other receptors such as KIT and various GPCRs may serve to prime mast cells for, or act as co-activators of, antigen-mediated mast cell activation. The signaling pathways linking Fc-epsilon-RI aggregation to human mast cell activation and function and how other receptors modify these Fc-mediated signaling events are not well understood. Thus the primary focus of the research is the elucidation of signaling mechanisms associated with the activation of mast cells via the Fc-epsilon-RI and especially how the signaling pathways initiated by other receptors may integrate with those initiated by the Fc-epsilon-RI for synergistic mast cell activation and/or inhibition.  The ability of mast cells to impact disease states in vivo also depends on their growth and differentiation from their progenitor cells, migration of the mast cells to their resident tissues, and their survival at these sites. Therefore, the integrated receptor-mediated signaling events regulating these processes are also being examined.  Recent key observations have been made relating to the effect of IL-33 on human mast cell function, cytoskeletal rearrangement, and the MS4A2-containing gene locus.   These studies in part also resulted in identification of a novel mouse mast cell line which now has been reported and allows the study of normal and mutated KIT constructs. These cells originated from a bone marrow-derived mouse mast cell culture as a rapidly dividing mast cell sub-population. Over time, these cells lost KIT expression while continuing to express functional high affinity receptors for IgE. Retroviral transduction of the cells with a human KIT construct resulted in surface expression of human KIT which responded to human stem cell factor (SCF;KIT ligand).   In examining IL-33 on mast cell function, we discovered that long-term exposure of human and mouse mast cells to IL-33 results in a substantial reduction of mast cell activation in response to antigen.  This appears to be a consequence of MyD88-dependent attenuation of signaling processes necessary for mast cell activation including antigen-mediated calcium mobilization and cytoskeletal reorganization. These changes were related to down-regulation of the expression of PLCg1 and Hck.  Linkage analyses have implicated the MS4A2-containing gene locus (encoding for Fc-epsilon-RI) as a candidate for allergy susceptibility. We have identified a truncation of Fc-epsilon-RI (t-Fc-epsilon-RI) in humans which contains a putative calmodulin binding domain.  We thus sought to identify the role of this variant in mast cell function. We determined that t-Fc-epsilon-RI forms a complex with Fyn kinase, Gab2, p85 PI3K and -tubulin. Calmodulin bound to t-Fc-epsilon-RI in the presence of Ca2+ initiating phosphorylation, which was critical for t-Fc-epsilon-RI function. Confocal microscopy demonstrated localization of the t-Fc-epsilon-RI complex to the Golgi surrounding the centrosome after IgE-dependent and IgE-independent activation. Knockdown of t-Fc-epsilon-RI attenuated microtubule formation, degranulation and IL-8 production downstream of Ca2+ signals. These observations are consistent with the conclusion that t-Fc-epsilon-RI mediates Ca2+-dependent microtubule formation, which promotes degranulation and cytokine release.  Migration of mast cells to sites of inflammation is known to be regulated by chemotactic factors such as SCF. Despite inducing similar early signaling events to antigen, chemotactic factors (including SCF) produce minimal degranulation in the absence of other stimuli. We therefore investigated whether processes regulating mast cell chemotaxis are rate limiting for mast cell mediator release. In these experiments, we disrupted actin polymerization, a requirement for mast cell chemotaxis. We then examined chemotaxis and mediator release in human mast cells induced by antigen or SCF. We found and reported that disruption of actin polymerization minimally affected early signaling pathways, but attenuated SCF-induced human mast cell chemotaxis. Unexpectedly, in the absence of other stimuli, SCF induced substantial degranulation in a concentration-dependent manner following actin disassembly. We interpreted this data as consistent with the conclusion that processes regulating cell migration limit mast cell degranulation as a consequence of cytoskeletal reorganization.","ACTIVITY":"ZIA","ADMINISTERING_IC":"AI","APPLICATION_TYPE":"1","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"","BUDGET_START":"","BUDGET_END":"","CFDA_CODE":"","CORE_PROJECT_NUM":"ZIAAI000965","ED_INST_TYPE":"","FOA_NUMBER":"","FULL_PROJECT_NUM":"1ZIAAI000965-09","FUNDING_ICs":"NIAID:737593\\","FUNDING_MECHANISM":"Intramural Research","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES","NIH_SPENDING_CATS":"","ORG_CITY":"","ORG_COUNTRY":"","ORG_DEPT":"","ORG_DISTRICT":"","ORG_DUNS":"","ORG_FIPS":"","ORG_NAME":"NIAID EXTRAMURAL ACTIVITIES","ORG_STATE":"","ORG_ZIPCODE":"","PHR":"","PI_IDS":"6479447;","PI_NAMEs":"METCALFE, DEAN D;","PROGRAM_OFFICER_NAME":"","PROJECT_START":"","PROJECT_END":"","PROJECT_TERMS":"Actins;Affect;Affinity;Allergic inflammation;Antigens;Attenuated;attenuation;Binding (Molecular Function);Bone Marrow;Calmodulin;Cell Culture Techniques;Cell Degranulation;cell growth;Cell Line;cell motility;Cell physiology;Cell surface;Cells;Cellular biology;Centrosome;Chemotactic Factors;Chemotaxis;Complex;Confocal Microscopy;cytokine;Cytoskeletal Modeling;Data;Differentiation and Growth;Disease;DNA Sequence Rearrangement;Down-Regulation;Event;exposed human population;Fc epsilon RI;Fc Receptor;Genes;genetic linkage analysis;Goals;Golgi Apparatus;Health;Human;human stem cells;Hypersensitivity;IgE;IgE Receptors;IL8 gene;in vivo;Inflammation;Inflammation Mediators;Ligands;Link;mast cell;Mediating;Mediator of activation protein;Microtubules;migration;MS4A1 gene;Mus;Mutate;novel;Pathogenesis;Phosphorylation;Phosphotransferases;Play;polymerization;Population;Predisposition;Process;Production;Reaction;receptor;receptor-mediated signaling;release of sequestered calcium ion into cytoplasm;Reporting;Research;research study;response;retroviral transduction;Role;Signal Pathway;signal processing;Signal Transduction;Site;Stem Cell Factor;Stem cells;Stimulus;Surface;Time;Tissues;Tubulin;Variant","PROJECT_TITLE":"Identification of Critical Signaling Pathways Modulating Mast Cell Activation","SERIAL_NUMBER":"965","STUDY_SECTION":"","STUDY_SECTION_NAME":"","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"9","TOTAL_COST":"737593","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8761122","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): Levels of unintended fertility in the United States are high: half of all pregnancies and a third of all births are unintended, with higher levels among young adults and among race-ethnic-nativity minorities. Because unintended births are associated with negative health outcomes, higher rates of unintended fertility among minorities may exacerbate health disparities, and reducing unintended fertility has been a public health goal since the 1980s. Although the proximate determinants of unintended fertility are clear (sex without effective contraceptive use and carrying unintended pregnancies to term), the underlying causes of these behaviors, and of race-ethnic-nativity differences, are not well understood. Drawing on existing frameworks for understanding fertility differentials, this project proposes two key distal determinants - reproductive knowledge and fertility motivation - that may explain differences in unintended fertility across race-ethnic-nativity groups. The project wil test the hypotheses that race-ethnic-nativity minorities have lower reproductive knowledge and motivation to prevent pregnancy;that these differences widen during young adulthood;and that these distal determinants drive differences in the proximate determinants (primarily sex and contraception) and in fertility itself. This project moves beyond prior descriptive work to identif precursors of risky sexual behavior and unintended fertility during young adulthood, a life course stage that is highly variable yet understudied in the fertility literature. We also extend prior wok by incorporating both men and women as well as diverse race- ethnic-nativity groups. Our project will derive robust and consistent measures from three complementary datasets: the Relationship Dynamics and Social Life study (\"RDSL\";a population-based sample of women aged 18-19 residing in a Michigan county in 2008/09, followed weekly for 2.5 years), the National Longitudinal Study of Adolescent Health (\"Add Health\";youths enrolled in grades 7-12 in 1995 and reinterviewed in 1996, 2001/02, and 2007/08), and the 2009 National Survey of Reproductive and Contraceptive Knowledge (\"Fog Zone\";a national sample of unmarried men and women aged 18-29). First, the project will create equivalent measures of the distal determinants across surveys and race-ethnicity-nativity, using factor and latent class analyses guided by integrative data analysis techniques. Second, cross-lag regression models will be used to examine the stability of these constructs as young adults learn and gain new experiences that may affect their reproductive knowledge and fertility motivation. Third, this work will use event history models to identify the elements of fertility motivation and reproductiv health knowledge that are most predictive of risky sexual behavior and unintended births. Findings will guide future research and interventions in targeting those at risk for unintended fertility and highlighting the most crucial domains for intervention. To disseminate our findings t policymakers and practitioners, we will work with a consultant from the National Campaign to Prevent Teen and Unplanned Pregnancy, a nationally respected, politically neutral, private advocacy organization.        ","ACTIVITY":"R01","ADMINISTERING_IC":"HD","APPLICATION_TYPE":"1","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"09/03/2014","BUDGET_START":"09/05/2014","BUDGET_END":"06/30/2015","CFDA_CODE":"865","CORE_PROJECT_NUM":"R01HD078412","ED_INST_TYPE":"SCHOOLS OF ARTS AND SCIENCES","FOA_NUMBER":"PA-13-302","FULL_PROJECT_NUM":"1R01HD078412-01A1","FUNDING_ICs":"NICHD:323548\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT","NIH_SPENDING_CATS":"","ORG_CITY":"BOWLING GREEN","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"SOCIAL SCIENCES","ORG_DISTRICT":"05","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"BOWLING GREEN STATE UNIVERSITY","ORG_STATE":"OH","ORG_ZIPCODE":"434030001","PHR":"PUBLIC HEALTH RELEVANCE: Unintended fertility, particularly among race-ethnic-nativity minorities, is linked to lower health and well-being among adults, children, and families, and high unintended birth rates in the U.S. constitute a major public health problem. The proposed research seeks to identify the underlying mechanisms driving unintended fertility among young adults and understand the sources of race-ethnic-nativity disparities in unintended fertility.            ","PI_IDS":"7696545 (contact);8090326;","PI_NAMEs":"GUZZO, KAREN B (contact);HAYFORD, SARAH R;","PROGRAM_OFFICER_NAME":"KING, ROSALIND B","PROJECT_START":"09/05/2014","PROJECT_END":"06/30/2018","PROJECT_TERMS":"Address;Adolescence;Adolescent;Adolescent and Young Adult;Adult;advocacy organizations;Affect;aged;Attitude;Automobile Driving;Behavior;behavior change;Birth;Birth Rate;career;Child;child bearing;Collaborations;Communities;Contraceptive Agents;Contraceptive methods;Contraceptive Usage;County;Data;Data Analyses;Data Set;Differential Fertility;Distal;driving behavior;Elements;Employment;Enrollment;Ethnicity aspects;Event;experience;Factor Analysis;Family;Female;Fertility;Fertility Determinant;Fogs;Gender;Goals;Health;health disparity;health knowledge;high risk sexual behavior;improved;Intervention;Knowledge;Learning;Life;Life Cycle Stages;Link;Literature;Longitudinal Studies;Maternal and Child Health;Measures;Mediating;men;Michigan;Minority;Modeling;Motivation;Nature;Outcome;Personal Satisfaction;population based;Pregnancy;Pregnancy in Adolescence;prevent;Probability;public health medicine (field);public health priorities;public health relevance;public health research;Race;Recording of previous events;reproductive;Reproductive Process;Research;Risk;Sampling;sex;Sex Behavior;social;Source;Staging;Surveys;Techniques;Testing;Translating;unintended pregnancy;United States;Unmarried;Unplanned pregnancy;Variant;Woman;Work;young adult;Youth","PROJECT_TITLE":"Distal Determinants of Disparities in Unintended Fertility","SERIAL_NUMBER":"78412","STUDY_SECTION":"SSPA","STUDY_SECTION_NAME":"","SUBPROJECT_ID":"","SUFFIX":"A1","SUPPORT_YEAR":"1","TOTAL_COST":"323548","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8690156","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): Synaptic plasticity is a fundamental feature of the nervous system that underlies neural development, adaptation and learning. There is growing evidence that deficits in the mechanisms of synaptic plasticity are involved in the pathophysiology of many psychiatric disorders, from schizophrenia to mood disorders. For this reason, NIMH has established as one of his strategic research priorities the study of brain plasticity \"at the cellular, synaptic, circuit, and behavioral level,\" with the final goal of \"determining the neurobiological bases of these processes.\" This proposal will study humans and three animal models (flies, mice, rats) to test the novel and provocative idea that synaptic plasticity is adaptive up to a point, but beyond that point, or in vulnerable individuals, it can become maladaptive. The \"cost\" of synaptic plasticity is not often considered but may be crucial in the pathophysiology of psychiatric disorders, and will be assessed at the ultrastructural, cellular, circuit, and behavioral level. Our previous NIMH-funded work has established that the overall result of wake plasticity is a net increase in synaptic strength, which is renormalized by sleep. But what happens when plasticity is \"excessive,\" for instance because it is extended beyond the physiological range without intervening sleep? Based on preliminary results obtained in both animals and humans, we hypothesize that extended plasticity can lead to negative consequences on neuronal activity (OFF periods, performance deficits) and on cellular function/integrity (cellular stress, ultrastructural abnormalities). Aim 1 will use rats to test whether plasticity-dependent synaptic overload leads to the occurrence of neuronal OFF periods, local EEG slowing during wake, and performance impairment. It will also establish to what extent these effects are a region- specific consequence of plasticity, rather than a general effect of prolonged wake. Aim 2 will use high density (hd) EEG in humans to ask whether the local increase in EEG theta waves, which occurs during wake as a result of extended plasticity in specific brain circuits, leads to local performance deficits, locally increased sleep need, and o sleep-dependent restoration of function. Aim 3 will use flies and mice to test whether extending plasticity by prolonging wakefulness leads to cellular stress and subcellular damage, and whether doing so chronically under sleep restriction conditions leads to lasting cellular damage and cognitive deficits. Plasticity plays a central role in the life of every organism, but its coston neural structure and function may be substantial especially at vulnerable developmental times, such as adolescence, or in vulnerable populations, such as psychiatric patients. Demonstrating the cost of plasticity at the cellular and systems level will have clear practical implications forthe prevention and treatment of mental disorders.        ","ACTIVITY":"R01","ADMINISTERING_IC":"MH","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"05/19/2014","BUDGET_START":"06/01/2014","BUDGET_END":"05/31/2015","CFDA_CODE":"242","CORE_PROJECT_NUM":"R01MH099231","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"PA-11-260","FULL_PROJECT_NUM":"5R01MH099231-02","FUNDING_ICs":"NIMH:668090\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF MENTAL HEALTH","NIH_SPENDING_CATS":"","ORG_CITY":"MADISON","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"PSYCHIATRY","ORG_DISTRICT":"02","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF WISCONSIN-MADISON","ORG_STATE":"WI","ORG_ZIPCODE":"537151218","PHR":"PUBLIC HEALTH RELEVANCE: This proposal will study humans and three animal models (flies, mice, rats) to understand at the ultrastructural, cellular, circuit, and behavioral level te cost of synaptic plasticity, an aspect of plasticity that is not often considered but may be crucal in the pathophysiology of psychiatric disorders.            ","PI_IDS":"7710922;2094139 (contact);","PI_NAMEs":"CIRELLI, CHIARA;TONONI, GIULIO  (contact);","PROGRAM_OFFICER_NAME":"VICENTIC, ALEKSANDRA ","PROJECT_START":"07/01/2013","PROJECT_END":"05/31/2018","PROJECT_TERMS":"Adolescence;Animal Model;Animals;Area;Automobile Driving;awake;base;Behavior;Behavioral;Brain;Brain region;Cell physiology;Cells;Cellular Stress;Chronic;Cognitive;Cognitive deficits;Confocal Microscopy;cost;Data;Decision Making;density;Development;Electroencephalography;Electron Microscopy;endoplasmic reticulum stress;experience;fly;Frequencies (time pattern);Functional disorder;Funding;Genes;Goals;Human;Impairment;Individual;Language;Lead;Learning;Life;Link;Mental disorders;Mental Health;Mitochondria;Molecular;Mood Disorders;Motor;Mus;National Institute of Mental Health (U.S.);Nature;Nervous system structure;neural circuit;Neurobiology;neurodevelopment;Neurons;Normal Range;novel;Organelles;Organism;Patients;Pattern;Performance;performance tests;Physiological;Plastics;Play;Prevention;Process;public health relevance;Rattus;relating to nervous system;Research Priority;restoration;Rodent;Role;Scalp structure;Schizophrenia;Side;simulation;Sleep;stem;Stress;Structure;Synapses;Synaptic plasticity;System;Testing;Time;Vertebral column;voltage;Vulnerable Populations;Wakefulness;Work","PROJECT_TITLE":"The cost of plasticity: from cells to systems","SERIAL_NUMBER":"99231","STUDY_SECTION":"NNRS","STUDY_SECTION_NAME":"Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"2","TOTAL_COST":"668090","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8731717","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): Shigella spp. cause disease by invading and multiplying within human colonic epithelial cells. Successful infection requires appropriate timing of virulence gene expression and the efficient acquisition of nutrients within the host;however, the sensing and acquisition of carbon sources and other nutrients by Shigella during infection is poorly understood. This application focuses on the role of carbon metabolism pathways in the virulence of Shigella flexneri. Our data suggest that S. flexneri uses information about the available carbon sources to determine the attachment and initial steps in invasion of host epithelial cells. Once inside the host cells, the bacteria must adjust their metabolism to take advantage of the different carbon sources available in the intracellular environment. The carbon and other nutrient sources present in the host cell cytoplasm and the pathways used by intracellular Shigella to obtain these sources are largely unknown. The first specific aim is to define the carbon and nutrient sources available to S. flexneri in the intracellular environment of the host. Using metabolomics, we can assess the nutrients present in the cytoplasm of uninfected cells and follow changes in the metabolome during the course of infection. Once we have identified the carbon sources that are present, our second aim is to determine the pathways the bacteria use to assimilate these nutrients. We will use proteomic and transcriptomic analysis of the intracellular bacteria to define the carbon metabolism genes expressed by intracellular S. flexneri. These will be complemented by genetic analysis to determine which of the expressed pathways are required for, or contribute to, intracellular growth. We will construct mutants that are defective in one or more of the carbon metabolism genes expressed intracellularly and test their ability to invade and cause plaques. The third aim is to determine the mechanism by which a regulator of central carbon metabolism, Cra, is linked to S. flexneri invasion and cell-to-cell spread. A mutation in cra markedly increased S. flexneri adherence to epithelial cells but limited cell-to-cell spread, pointing to a link between S. flexnei carbon metabolism and virulence. We will use genetic and biochemical characterization of the cra mutant to determine the mechanism of Cra's effect on virulence. Taken together, the data generated in this study will provide essential information on carbon metabolism and its role in Shigella virulence, and will contribute significantly to our broader understanding of the physiology and metabolism of S. flexneri in the host cell environment. Such data are applicable to the design of therapeutics targeting intracellular S. flexneri, as well as to the design of vaccines based on antigens expressed when the bacteria are growing within host cells.        ","ACTIVITY":"R01","ADMINISTERING_IC":"AI","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"07/29/2014","BUDGET_START":"09/01/2014","BUDGET_END":"08/31/2015","CFDA_CODE":"855","CORE_PROJECT_NUM":"R01AI016935","ED_INST_TYPE":"SCHOOLS OF ARTS AND SCIENCES","FOA_NUMBER":"PA-11-260","FULL_PROJECT_NUM":"5R01AI016935-30","FUNDING_ICs":"NIAID:381345\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES","NIH_SPENDING_CATS":"","ORG_CITY":"AUSTIN","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"BIOLOGY","ORG_DISTRICT":"25","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF TEXAS, AUSTIN","ORG_STATE":"TX","ORG_ZIPCODE":"787121532","PHR":"PUBLIC HEALTH RELEVANCE: Shigella flexneri and related species are major sources of human diarrheal disease, affecting more than 100,000,000 people each year. This bacterium infects and grows within human intestinal epithelial cells, but many steps in this process are poorly understood. By characterizing the mechanisms of nutrient sensing and nutrient acquisition in the host cells, we will gain important knowledge about adaptation of bacteria to the host environment and potential means for interrupting the disease process.                ","PI_IDS":"1892580;","PI_NAMEs":"PAYNE, SHELLEY M.;","PROGRAM_OFFICER_NAME":"MILLS, MELODY ","PROJECT_START":"09/30/1980","PROJECT_END":"08/31/2018","PROJECT_TERMS":"Acute;Adherence (attribute);Affect;Antigens;B-Lymphocytes;Bacteria;base;Biochemical;Biological Process;Biology;Carbon;Cells;Complement;Coupled;Cytoplasm;Cytosol;Data;Defect;design;detection of nutrient;Disease;Environment;Epithelial Cells;Epithelium;Gene Expression;Genes;Genetic;genetic analysis;Growth;Human;In Vitro;Infection;Inflammatory Response;Intestines;Invaded;Iron;Knowledge;Lead;Life;Life Style;Link;Location;Mammalian Cell;Measures;Metabolic;Metabolic Pathway;Metabolism;metabolomics;Molecular Profiling;mutant;Mutation;Nutrient;pathogen;Pathway interactions;Physiology;Process;protein profiling;Proteins;Proteomics;public health relevance;Role;Shigella;Shigella flexneri bacterium;Signal Transduction;Source;sugar;Testing;Therapeutic Intervention;therapeutic target;Time;transcriptomics;uptake;Vaccine Design;Vaccines;Virulence","PROJECT_TITLE":"Role of carbon metabolism in virulence of Shigella flexneri","SERIAL_NUMBER":"16935","STUDY_SECTION":"ZRG1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"30","TOTAL_COST":"381345","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8698894","ABSTRACT_TEXT":"   DESCRIPTION (provided by the applicant):  Psoriasis, a highly prevalent disease of humans of unknown cause, is a chronic inflammatory disorder primarily involving skin, with distinctive clinical characteristics. With the newly developed tools that facilitate microbiome research, it now is possible to assess whether the cutaneous microbiome plays a role in the pathogenesis of this disorder. Preliminary data from our studies suggest that the cutaneous microbiome in psoriasis is complex and possibly different from normal. To deal with this complexity, we propose to examine the cutaneous microbiome in relation to psoriasis with explorations at several taxonomic and informatic levels. Our overall objective is to examine how changes in the normal cutaneous microbiome contribute to the pathogenesis of psoriasis. Since causality is complex and often difficult to prove, and beyond the scope of this RFP, our overall hypothesis is that there are alterations in the cutaneous microbiome in areas of skin affected by psoriasis in comparison with the range observed in clinically unaffected areas, or in healthy persons. We also hypothesize that the characteristics of the microbiome may affect clinical responses to the immunomodulatory agents used to treat psoriasis. An alternative hypothesis is that effective treatment of psoriasis with systemic immunomodulatory agents will not substantially affect the disordered microbial ecosystem. Such observations would provide evidence for the roles of the microbiota in this disorder. Since an important consideration in microbiome research is the optimal level (e.g. phylum, genus, species, strain, gene) at which to examine a scientific question, and we are not yet certain what are the optimal levels for psoriasis, this also will be examined. Our studies of psoriasis should allow development of both approaches and tools that will have general utility for microbiome research. To test our hypothesis, we propose the following specific aims: 1. To understand the cutaneous microbiome species composition overlaying psoriatic lesions;2. To investigate differences in metagenome content for psoriatic lesions compared to normal skin;3. To identify differences in the transcriptional profiles of the microbiome and the host between normal skin and psoriatic lesions using high-throughput sequencing;and 4. To estimate the effects of systemic immunomodulatory therapy for psoriasis on microbiome composition. In total, these studies should help us understand the role of the microbiome in psoriasis pathogenesis. PUBLIC HEALTH RELEVANCE: This is a project to understand the microbiology of psoriasis using molecular and genomic methods. We will compare patients with psoriasis and healthy individuals to learn the microbial species, genes, and gene products on the skin that differ between them.            ","ACTIVITY":"UH2","ADMINISTERING_IC":"AR","APPLICATION_TYPE":"3","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"12/04/2013","BUDGET_START":"12/05/2013","BUDGET_END":"08/31/2015","CFDA_CODE":"095","CORE_PROJECT_NUM":"UH2AR057506","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"RFA-RM-08-012","FULL_PROJECT_NUM":"3UH2AR057506-01S3","FUNDING_ICs":"OD:187506\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES","NIH_SPENDING_CATS":"","ORG_CITY":"NEW YORK","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"INTERNAL MEDICINE/MEDICINE","ORG_DISTRICT":"12","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"NEW YORK UNIVERSITY SCHOOL OF MEDICINE","ORG_STATE":"NY","ORG_ZIPCODE":"100165802","PHR":" Narrative This is a project to understand the microbiology of psoriasis using molecular and genomic methods. We will compare patients with psoriasis and healthy individuals to learn the microbial species, genes, and gene products on the skin that differ between them.","PI_IDS":"6666183;","PI_NAMEs":"BLASER, MARTIN J;","PROGRAM_OFFICER_NAME":"BAKER, CARL ","PROJECT_START":"12/05/2013","PROJECT_END":"08/31/2015","PROJECT_TERMS":"adalimumab;Affect;Area;Bacteria;Characteristics;Chronic;Clinical;Communities;Complex;Cutaneous;Data;Development;Disease;Ecosystem;effective therapy;Etiology;Evaluation;Failure (biologic function);fungus;Gene Expression Profile;Genes;Genomics;Health;High-Throughput Nucleotide Sequencing;human disease;Immunologics;Individual;Inflammatory;Informatics;Learning;Lesion;Massive Parallel Sequencing;metagenome;metagenomic sequencing;Methods;microbial;Microbiology;microbiome;Molecular;Pathogenesis;Pathway Analysis;Pathway interactions;Patients;Persons;Phylogenetic Analysis;Play;Process;Proteins;Psoriasis;Relative (related person);Research;response;Ribosomal RNA;Role;Secondary to;Skin;standard of care;success;Techniques;Testing;Time;Tissues;tool;Treatment outcome;Variant","PROJECT_TITLE":"Evaluation of the cutaneous microbiome in psoriasis","SERIAL_NUMBER":"57506","STUDY_SECTION":"ZRG1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"S3","SUPPORT_YEAR":"1","TOTAL_COST":"187506","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8622088","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): Lysosomal storage diseases (LSDs) result from genetic mutations in one of 42 different lysosomal proteins, 12 of which are involved in the enzymatic catabolism or degradation of sphingolipids and glycosphingolipids (GSLs). Although fully two-thirds of all LSDs have some CNS involvement that can result in progressive cognitive and motor decline, there are currently no effective therapies. There are, however, two effective approaches to treating LSDs in the periphery. The first is enzyme replacement therapy (ERT), in which the defective enzyme is supplemented with recombinant protein that has been terminally modified to be taken up into the lysosome. The second approach entails inhibition of GSL synthesis with small molecules (substrate reduction therapy or SRT), and this strategy has been clinically proven to be effective for the treatment of Gaucher type 1 disease. To date SRT has focused on inhibition of glucosylceramide (GlcCer) synthase, which catalyzes the first step in GSL synthesis. The only approved agent, miglustat, is a weak inhibitor which has limited efficacy only against Gaucher type 1 and possesses some off-target effects. A much more potent and selective inhibitor, eliglustat tartrate, is currently in phase 3 clinical trials for Gacher type 1 with reported efficacy superior to that of the ERT agent, imiglucerase. Unfortunately, eliglustat tartrate does not penetrate the CNS, so holds no promise for treating CNS-based LSDs. We recently demonstrated that a structural analog of eliglustat (CCG-203586), designed to be more CNS-permeable, was able to effect measurable reductions in GlcCer levels in the brains of mice. However, based on its close structural relationship to eliglustat, which is known to be rapidly metabolized in mice, it is unlikely that CCG-203586 will be an optimal probe for studying chronic inhibition of GSL synthesis in murine models of CNS-based LSDs. The overarching goal of this work will be to determine if SRT is an effective approach to ameliorating the symptoms of LSDs of the CNS. Our approach will be to: 1) optimize the CCG-203586 lead structure for metabolic stability and CNS-permeability without sacrificing potency, 2) evaluate the best new analogs for their degree of penetrance into the CNS of mice, and 3) select optimal probes for long-term studies in mouse models of the CNS-based LSDs: Sandhoff and Tay-Sachs. Our proposal is innovative in its use of physical property-based design to reduce recognition by efflux transporters (e.g. MDR1) at the blood brain barrier, and by the use of dual cell-based assays for GlcCer synthase inhibition that simultaneously measure both activity and recognition by MDR1. This work will be significant in allowing, for the first time, investigation o the effects of chronic inhibition of GlcCer synthase in the CNS on GSL dynamics and on development and progression of symptoms in animal models of CNS-based LSDs. Finally, the ultimate impact of our work will be progress toward the first therapy for an unmet medical need, viz. CNS-based glycosphingolipidoses.        ","ACTIVITY":"R01","ADMINISTERING_IC":"HD","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"03/25/2014","BUDGET_START":"04/01/2014","BUDGET_END":"03/31/2015","CFDA_CODE":"865","CORE_PROJECT_NUM":"R01HD076004","ED_INST_TYPE":"SCHOOLS OF PHARMACY","FOA_NUMBER":"PAR-12-060","FULL_PROJECT_NUM":"5R01HD076004-02","FUNDING_ICs":"NICHD:607880\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT","NIH_SPENDING_CATS":"","ORG_CITY":"ANN ARBOR","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"PHARMACOLOGY","ORG_DISTRICT":"12","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF MICHIGAN","ORG_STATE":"MI","ORG_ZIPCODE":"481091274","PHR":"PUBLIC HEALTH RELEVANCE: The mission of the NINDS is to reduce the burden of neurological disease. Currently, patients suffering from the devastating effects of neuronopathic lysosomal storage diseases (e.g. Sandhoff and Tay Sachs) have no effective treatment options. We propose to develop CNS-permeable in vivo probes to study whether synthesis inhibition therapy, which has been shown to be effective at treating lysosomal storage disease outside of the CNS, is a viable option for treating CNS-based diseases. A successful outcome of our aims would significantly advance a new therapeutic approach for an unmet medical need in the area of neurological disease.            ","PI_IDS":"9482690 (contact);1877089;","PI_NAMEs":"LARSEN, SCOTT D (contact);SHAYMAN, JAMES ALAN;","PROGRAM_OFFICER_NAME":"TSILOU, KATERINA ","PROJECT_START":"04/01/2013","PROJECT_END":"03/31/2016","PROJECT_TERMS":"ABCB1 gene;Acute;alkalinity;Amines;analog;Animal Model;Area;Attenuated;base;Biological Assay;Blood - brain barrier anatomy;Brain;Catabolism;Cells;Ceramide glucosyltransferase;Chronic;clinical efficacy;Cognitive;design;Development;Disease;Disease model;Dose;Drug Kinetics;effective therapy;enzyme replacement therapy;Enzymes;G(M2) Ganglioside;Gangliosides;Gangliosidosis GM1;Gene Mutation;Glucosylceramides;glycosphingolipidoses;Glycosphingolipids;Goals;Hemoglobin;imiglucerase;improved;In Vitro;in vitro Assay;in vivo;inhibitor/antagonist;innovation;Investigation;Kidney;Lead;Liver;Liver Microsomes;Longitudinal Studies;lysosomal proteins;Lysosomal Storage Diseases;Lysosomes;Measurable;Measures;Medical;Metabolic;Metabolic Clearance Rate;Metabolism;Miglustat;Mission;Modeling;Motor;mouse model;Mus;National Institute of Neurological Disorders and Stroke;nervous system disorder;Neutral Glycosphingolipids;Non-Neuronopathic Gaucher Disease;novel;novel therapeutic intervention;Outcome;P-Glycoprotein;Patients;Penetrance;Peripheral;Permeability;pharmacophore;Phase II Clinical Trials;Phase III Clinical Trials;physical property;Plasma;Property;Proteins;public health relevance;Recombinant Proteins;Reporting;response;Rodent;Site;small molecule;Sphingolipids;Spleen;Structure;Symptoms;Tartrates;Therapeutic;Thrombocytopenia;Time;treatment strategy;Wild Type Mouse;Work","PROJECT_TITLE":"Novel Probes for Studying Treatment of CNS-based Lysosomal Storage Diseases","SERIAL_NUMBER":"76004","STUDY_SECTION":"ZRG1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"2","TOTAL_COST":"607880","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8643245","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant):  The goal of this project is to enable the investigation of the solvation and electrostatic properties of macromolecules in biomedical research by supporting the maintenance and continued development of the open-source Adaptive Poisson-Boltzmann Solver and PDB2PQR software packages. An understanding of electrostatic interactions is essential for the study of biomolecular processes. The structures of proteins and other biopolymers are being determined at an increasing rate through structural genomics and other efforts while specific linkages of these biopolymers in cellular pathways or supramolecular assemblages are being detected by genetic and proteomic studies. To integrate this information in physical models for drug discovery or other applications requires the ability to evaluate the energetic interactions within and between biopolymers. Among the various components of molecular energetics, solvation properties and electrostatic interactions are of special importance due to the long range of these interactions and the substantial charges of typical biopolymer components. APBS is a unique software package which solves the equations of continuum electrostatics for large biomolecular assemblages. This software was designed \"from the ground up\" using modern design principles to ensure its ability to interface with other computational packages and evolve as methods and applications change over time. The APBS code is accompanied by extensive documentation for both users and programmers and is supported by a variety of utilities for preparing calculations and analyzing results. Finally, the free, open-source APBS license ensures its accessibility to the entire biomedical community. The use of continuum solvation methods such as APBS requires accurate and complete structural data as well as force field parameters such as atomic charges and radii. PDB2PQR provides a software solution for such parameterization as well as biomolecular titration state assignment and visualization capability to support use by researchers with a wide range of expertise.        ","ACTIVITY":"R01","ADMINISTERING_IC":"GM","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"03/13/2014","BUDGET_START":"03/01/2014","BUDGET_END":"02/28/2015","CFDA_CODE":"859","CORE_PROJECT_NUM":"R01GM069702","ED_INST_TYPE":"","FOA_NUMBER":"PAR-11-028","FULL_PROJECT_NUM":"5R01GM069702-12","FUNDING_ICs":"NIGMS:448465\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES","NIH_SPENDING_CATS":"","ORG_CITY":"RICHLAND","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"04","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"BATTELLE PACIFIC NORTHWEST LABORATORIES","ORG_STATE":"WA","ORG_ZIPCODE":"993520999","PHR":"PUBLIC HEALTH RELEVANCE: Electrostatics plays an important role in all molecular-scale phenomena and therefore is integral to the analysis of biomolecular structure and interactions, including the study of health-related protein mutations and design of new molecular therapies. This project supports models for understanding electrostatics and solvation through the continued development of the open-source APBS and PDB2PQR software packages.            ","PI_IDS":"7215157;","PI_NAMEs":"BAKER, NATHAN A.;","PROGRAM_OFFICER_NAME":"PREUSCH, PETER ","PROJECT_START":"01/15/2004","PROJECT_END":"02/28/2017","PROJECT_TERMS":"Address;Adoption;Algorithms;base;Biomedical Research;Biopolymers;Charge;Code;Communities;Computational Biology;Computer software;Data;Databases;design;Development;Documentation;drug discovery;Electrostatics;Ensure;Equation;Feedback;Funding;Genetic;Goals;Health;Hydrogen Bonding;Imagery;improved;Investigation;Licensing;macromolecule;Maintenance;Methods;Modeling;Molecular;molecular scale;Molecular Structure;Mutation;nanoscale;open source;Output;Pathway interactions;physical model;Play;Preparation;Process;Property;protein structure;Proteins;Proteomics;public health relevance;Radial;Research Personnel;Research Support;Role;Services;simulation;simulation software;Solutions;structural genomics;Structure;Time;Titrations;Update","PROJECT_TITLE":"APBS: Nanoscale Biomolecular Electrostatics Software","SERIAL_NUMBER":"69702","STUDY_SECTION":"BDMA","STUDY_SECTION_NAME":"Biodata Management and Analysis Study Section","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"12","TOTAL_COST":"448465","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8588278","ABSTRACT_TEXT":"   DESCRIPTION (provided by applicant): We know much about HIV transcription and replication. During the past two decades, the roles played by basal transcription complexes, NF-kB and Tat in initiation and elongation of viral transcription have been placed on solid scientific foundation. In addition, the co-activator of NF-kB and the viral transactivator Tat, the positive transcription elongation factor b (P-TEFb), has been demonstrated to phosphorylate the C-terminal domain (CTD) of RNA polymerase II (RNAPII), Spt5 from DSIF and RD from NELF, thus allowing transcription complexes to elongate. P-TEFb itself is under exquisite control in cells, which determines their state of differentiation and proliferation. At least three additional cyclin dependent kinases play a critical role in co- transcriptional processing of HIV RNA, namely Cdk11, 12 and 13, some of which affect 3'end formation (Cdk11) and others the complex splicing of viral transcripts (Cdk12/Cdk13). Recently, we found that the latter two bind CycK, which was thought previously to be another component of P-TEFb. Importantly, CycK does not bind Cdk9, which together with CycT1 or CycT2 forms P-TEFb. This proposal will address in intricate detail how Tat interferes with the formation of inactive P-TEFb complexes in cells, how certain inhibitors of histone deacetylases do the same and how these new CycK complexes affect the splicing of HIV transcripts. In the process, we will have learned how Tat sustains optimal viral replication in infected cells, how drugs such as HMBA, SAHA and specific HDACis perturb the metabolism of P-TEFb and how these new CycK:Cdk complexes affect RNAPII as well as alternative splicing factors. New targets for inhibiting HIV replication will be revealed together with candidate compounds that should find future clinical utility.      ","ACTIVITY":"R01","ADMINISTERING_IC":"AI","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"11/20/2013","BUDGET_START":"12/01/2013","BUDGET_END":"11/30/2014","CFDA_CODE":"855","CORE_PROJECT_NUM":"R01AI049104","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"PA-10-067","FULL_PROJECT_NUM":"5R01AI049104-13","FUNDING_ICs":"NIAID:386250\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES","NIH_SPENDING_CATS":"","ORG_CITY":"SAN FRANCISCO","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"INTERNAL MEDICINE/MEDICINE","ORG_DISTRICT":"12","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF CALIFORNIA, SAN FRANCISCO","ORG_STATE":"CA","ORG_ZIPCODE":"941430962","PHR":"PUBLIC HEALTH RELEVANCE: Tat transactivation is essential for HIV replication. Tat binds CycT1 and Cdk9 that convert an initiating to an elongating RNA polymerase II. Next, CycK binds Cdk12 and Cdk13 that regulate the co-transcriptional processing of HIV transcripts. This proposal will investigate how Tat uses these complexes for optimal HIV replication and how these Cdks could be manipulated pharmacologically in the future.         ","PI_IDS":"1969643;","PI_NAMEs":"PETERLIN, BORIS MATIJA;","PROGRAM_OFFICER_NAME":"SHARMA, OPENDRA K.","PROJECT_START":"01/01/2001","PROJECT_END":"11/30/2015","PROJECT_TERMS":"Acetylation;Acquired Immunodeficiency Syndrome;Address;Adverse effects;Affect;Alternative Splicing;Anabolism;Binding (Molecular Function);Biological Assay;Biology;C-terminal;Cell physiology;Cells;Cellular Stress;Clinical;Complex;Cues;Cyclin-Dependent Kinases;Dissociation;Elongation Factor;Event;extracellular;Feedback;Fluorescence;Foundations;Future;Genetic;Genetic Transcription;Genomics;HDAC6 gene;Heat-Shock Proteins 90;Hexamethylene Bisacetamide;Histone Deacetylase;Histone Deacetylase Inhibitor;Histones;HIV;inhibitor/antagonist;Investigation;Knowledge;Lead;Learning;Life;Metabolism;negative elongation factor;NF-kappa B;novel strategies;particle;Pathway interactions;Pharmaceutical Preparations;Phosphorylation;Phosphotransferases;Play;Polyadenylation;Positive Transcriptional Elongation Factor B;Prevention;Process;Production;Proteins;public health relevance;Reagent;Regulation;Replication-Associated Process;RNA;RNA Polymerase II;RNA Splicing;Role;Signal Pathway;Signal Transduction;Small Nuclear RNA;Solid;System;Theft;therapeutic target;Trans-Activation (Genetics);Trans-Activators;Transcript;Transcription Elongation;Tubulin;tumor;United States National Institutes of Health;Viral;virology;Vorinostat;Work","PROJECT_TITLE":"TAT Transactivation","SERIAL_NUMBER":"49104","STUDY_SECTION":"AMCB","STUDY_SECTION_NAME":"AIDS Molecular and Cellular Biology Study Section","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"13","TOTAL_COST":"386250","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8832125","ABSTRACT_TEXT":"DESCRIPTION (provided by applicant): We are developing nanoscale electronic circuits (nanofids) that will be implanted into millions of neurons to record neural activity during behavior. Our long-term goal is to record high-resolution neural activity information during acquisition and expression of learned behavioral models of addiction. The long-term health goal is to identify neuronal ensembles encoding addiction-related memories for eventual ablation. In this application, we are developing semiconductor chip prototypes that will transmit near-infrared (NIR) signals with unique frequency identification whenever intracellular calcium levels rise above a set threshold corresponding to neural activation. We are assessing power requirements and biocompatibility of the overall circuit and individual circuit components in air and intracellular model solutions. Signal attenuation of NIR output will be assessed in these solutions using NIR spectrometry. In future, the optimized circuit from this application will be incorporated into millions of devices that will be implanted into neurons for intracellular recordig of neural activity in brain during behavior.","ACTIVITY":"R43","ADMINISTERING_IC":"DA","APPLICATION_TYPE":"1","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"09/10/2014","BUDGET_START":"09/15/2014","BUDGET_END":"03/31/2015","CFDA_CODE":"279","CORE_PROJECT_NUM":"R43DA038906","ED_INST_TYPE":"","FOA_NUMBER":"PA-14-071","FULL_PROJECT_NUM":"1R43DA038906-01","FUNDING_ICs":"NIDA:158895\\","FUNDING_MECHANISM":"SBIR-STTR","FY":"2014","IC_NAME":"NATIONAL INSTITUTE ON DRUG ABUSE","NIH_SPENDING_CATS":"","ORG_CITY":"SAN DIEGO","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"52","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"GALIANA TECHNOLOGY, INC.","ORG_STATE":"CA","ORG_ZIPCODE":"921103507","PHR":"PUBLIC HEALTH RELEVANCE: We are developing nanoscale electronic circuits for large-scale intracellular recording of neural activity during behavior. Our long-term goal is to record high-resolution neural activity information during acquisition and expression of learned behavioral models of addiction. The long-term health goal is to identify neuronal ensembles1 encoding addiction-related memories in human addicts for eventual ablation.","PI_IDS":"12060675;","PI_NAMEs":"WELLS, MARK;","PROGRAM_OFFICER_NAME":"BOUGH, KRISTOPHER J.","PROJECT_START":"09/15/2014","PROJECT_END":"03/31/2015","PROJECT_TERMS":"Ablation;addiction;Air;Animal Model;Animals;Association Learning;attenuation;base;Behavior;Behavioral Model;biomaterial compatibility;Biomedical Engineering;Brain;Calcium;Calcium Binding;Calmodulin;Capsid;Capsid Proteins;Cathodes;Cells;Characteristics;cofactor;Computer Analysis;Cues;design;detector;Devices;Electron Transport;Electronics;Electrons;Energy-Generating Resources;Enzymes;Evaluation;Flavin Mononucleotide;Flavin-Adenine Dinucleotide;Frequencies (time pattern);Fright;Future;Goals;Government;Health;Human;imaging modality;Implant;Individual;Laccase;learned behavior;Learning;Marketing;Mediating;Memory;memory encoding;Microelectrodes;Modeling;NADP;nanoscale;National Institute of Drug Abuse;Near-Infrared Spectroscopy;neuronal patterning;Neurons;Nitric Oxide Synthase;Output;Oxidoreductase;Pattern;Perception;Persons;Pharmaceutical Preparations;Play;Post-Traumatic Stress Disorders;Power Sources;Problem Solving;Process;prototype;Quantum Dots;Radio;relating to nervous system;Research;Resolution;Role;scale up;Semiconductors;Signal Transduction;Solutions;System;Technology;Viral;voltage","PROJECT_TITLE":"Electrical circuit prototype for nanoscale intracellular neural recording device","SERIAL_NUMBER":"38906","STUDY_SECTION":"ZRG1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"1","TOTAL_COST":"158895","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8868210","ABSTRACT_TEXT":"DESCRIPTION (provided by applicant): The proposed project is a partnership between prevention scientists and the Cherokee Nation Behavioral Health Services to create, implement and evaluate a new, integrated community-level intervention designed to prevent underage drinking and associated negative consequences among American Indian and white youth living in rural high-risk underserved communities. This trial will take place in northeastern Oklahoma, an area suffering from high rates of poverty and substantial health disparities. The proposed intervention builds directly on the results of multiple previous experiments with two distinct approaches-community environmental change and brief intervention and referral-evaluated alone and in combination using a factorial design. Direct- action community organizing, documented as effective in multiple previous randomized trials, will be used to address community issues related to alcohol use and commercial and social access to alcohol among adolescents. Our design and implementation of brief interventions differs in a fundamental way from typical implementations. Instead of SBIRT implemented in select limited numbers of clinics, emergency departments or schools, we will design a community-wide SBIRT intervention. The population-level brief interventions will include five key components: (1) brief one-on-one screening and motivational interviewing sessions, (2) gatekeeper training, (3) peer leader training, (4) family postcard campaign, and (5) community-wide media campaign. Five key research design elements optimize causal inference and experimental evaluation of the intervention effects: (1) a controlled interrupted time-series design, (2) random selection of towns, (3) random assignment to study condition, (4) a factorial design, and (5) multiple comparison groups. The primary design feature of this randomized trial is a controlled interrupted time-series design. The large number of repeated measures (a time-series) substantially increases internal validity (i.e., strength of causal inference) as well as statistical power over conventional pre/post community trial designs. Repeated assessments will measure implementation fidelity for each intervention component, and measure key proximal as well as the primary ultimate outcomes through survey, observation and archival sources. The primary study sample will include all high-school students within study towns. Weekly and monthly measurements will produce a time-series design with observations of youth nested within town over the four-year period. In addition to repeated cross-sectional samples, we will use participant identifiers to track the embedded cohorts over the four years. This innovative project, involving a strong partnership between established prevention scientists and leaders of the Cherokee Nation Behavioral Health Services, has the potential to transform alcohol prevention research and practice. Despite advances in prevention science and practices in recent decades, the U.S. continues to struggle with significant alcohol-related risks and consequences among youth. The proposed project will provide a rigorous evaluation of a new, integrated community-level preventive intervention.","ACTIVITY":"R01","ADMINISTERING_IC":"AA","APPLICATION_TYPE":"3","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"06/20/2014","BUDGET_START":"07/01/2014","BUDGET_END":"06/30/2015","CFDA_CODE":"310","CORE_PROJECT_NUM":"R01AA020695","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"RFA-AA-11-001","FULL_PROJECT_NUM":"3R01AA020695-04S1","FUNDING_ICs":"OD:99809\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM","NIH_SPENDING_CATS":"","ORG_CITY":"GAINESVILLE","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"OTHER HEALTH PROFESSIONS","ORG_DISTRICT":"03","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF FLORIDA","ORG_STATE":"FL","ORG_ZIPCODE":"326115500","PHR":"The proposed project is a close partnership between prevention scientists and the Cherokee Nation Behavioral Health Services to create, implement and evaluate a new, integrated community-level intervention designed to prevent underage drinking and associated negative consequences among multi-ethnic youth living in rural, high-risk underserved communities. The intervention will include community strategies to reduce access to alcohol and high-risk situations, and community-wide implementation of brief interventions and referral. This innovative project has the potential to transform alcohol prevention research and practice, as the U.S. continues to struggle with significant alcohol-related risks and consequences among youth.","PI_IDS":"6204217;","PI_NAMEs":"KOMRO, KELLI ANN;","PROGRAM_OFFICER_NAME":"SCOTT, MARCIA S.","PROJECT_START":"09/15/2011","PROJECT_END":"06/30/2016","PROJECT_TERMS":"Accident and Emergency department;Address;Adolescent;Age;alcohol availability;Alcohol consumption;alcohol prevention;Alcohols;American Indians;Area;base;behavioral health;brief intervention;Cherokee Indian;Clinic;Clinical Trials Design;cohort;Communities;Community Actions;community based participatory research;community intervention;Community Trial;comparison group;control trial;cost;Country;Data Collection;data management;design;Diffusion;Disadvantaged;Drug Addiction;Effectiveness;Elements;Environment;environmental change;environmental intervention;Evaluation;evidence base;Family;Family history of;Future;Gatekeeping;Gender;Goals;health disparity;Health Services;Health Services for the Aged;high risk;High School Student;Individual;Information Systems;innovation;Internet;Intervention;intervention effect;Intervention Studies;Lead;Leadership;Life;Measurement;Measures;Media Campaign;Mentors;Mentorship;Methods;Modeling;motivational enhancement therapy;Oklahoma;Outcome;Outcome Measure;Participant;peer;Population;Poverty;Prevention;Prevention Research;Preventive;Preventive Intervention;programs;Protocols documentation;Random Allocation;randomized trial;Records;Research;Research Design;Research Personnel;Research Project Grants;research study;Risk;Risk Factors;Rural;Rural Community;Sampling;Sampling Studies;Schools;Science;Scientist;screening;screening and brief intervention;screening, brief intervention, referral, and treatment;Series;social;Socioeconomic Status;socioeconomics;Source;Survey Methodology;Surveys;System;Technology;Testing;therapy design;Time;Training;underage drinking;underage drinking prevention;United States National Institutes of Health;Work;Youth;youth access to alcohol","PROJECT_TITLE":"Cherokee Nation Prevention Trial: Interactive Effects of Environment &SBIRT","SERIAL_NUMBER":"20695","STUDY_SECTION":"ZAA1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"S1","SUPPORT_YEAR":"4","TOTAL_COST":"99809","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8936209","ABSTRACT_TEXT":"DESCRIPTION (provided by applicant): The Center for Synchrotron Biosciences (CSB), with state-of-the-art facilities and laboratories at the National Synchrotron Light Source (NSLS) and at Case Western Reserve University (CWRU), proposes to continue its programs of developing and operating a suite of synchrotron beamlines and associated technologies at Brookhaven National Laboratories (BNL) through a renewal of its P30 Center grant. Since 1994, with continuous funding from the NIH (NCRR/NIBIB), significant support from NSF and in partnership with many academic institutions and BNL, the Center has supported a large, international structural biology user community through the design, construction, and operation of multiple beamlines. The Center serves over 500 life-science users at the NSLS through the continuous upgrade, maintenance, and operation of beamlines that provide photons, advanced end-station instrumentation, and user support and training for a range of synchrotron biophysics technologies at the state-of-the-art. In this renewal proposal, the CSB will continue technology sores for: synchrotron X-ray footprinting, X-ray spectroscopy, and macromolecular crystallography. An Administrative Core will support these cores and Dissemination and Training Cores will supplement their activities. In the Research Base, for the three cores overall, we identify 176 Pls with 245 specific sources of funding (projects) including 230 peer-reviewed project grants (~200 from NIH). We propose to support 145 projects in macromolecular crystallography (100 PIs), 52 projects in X-ray footprinting (43 PIs), and 48 projects in X-ray spectroscopy (33 PIs) for the renewal.     The opportunity to considerably enhance the facilities available to this Research Base is based on a once in a generation opportunity provided by the opening of a new synchrotron ring, the NSLS-II. The CSB team, in collaboration with BNL has secured funding for new beamlines at this facility. During the first part of the renewal period, the CSB will complete beamline desig, purchase and fabricate equipment, and then by the mid-point of the grant period complete installation, then commission several state-of-the art beamlines. We will make the transition to vibrant user programs by the end of the grant period with robust scientific facilities, active dissemination and training program and novel scientific results. The outcome of the five-year period will be a Center that continues to be a magnet for world-class synchrotron biosciences research well beyond existing capabilities and productivity that can continue for many years into the future.","ACTIVITY":"P30","ADMINISTERING_IC":"EB","APPLICATION_TYPE":"3","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"09/27/2014","BUDGET_START":"09/30/2014","BUDGET_END":"08/31/2015","CFDA_CODE":"286","CORE_PROJECT_NUM":"P30EB009998","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"PAR-13-249","FULL_PROJECT_NUM":"3P30EB009998-06S1","FUNDING_ICs":"NIBIB:37800\\","FUNDING_MECHANISM":"Research Centers","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING","NIH_SPENDING_CATS":"","ORG_CITY":"CLEVELAND","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"GENETICS","ORG_DISTRICT":"11","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"CASE WESTERN RESERVE UNIVERSITY","ORG_STATE":"OH","ORG_ZIPCODE":"441067015","PHR":"PUBLIC HEALTH RELEVANCE STATEMENT (PROVIDED BY APPLICANT): The outcome of the five-year period will be a Center that continues to be a magnet for world-class synchrotron biosciences research well beyond existing capabilities and productivity that can continue for many years into the future.","PI_IDS":"2424126;","PI_NAMEs":"CHANCE, MARK R;","PROGRAM_OFFICER_NAME":"LIU, CHRISTINA ","PROJECT_START":"09/01/2009","PROJECT_END":"08/31/2019","PROJECT_TERMS":"base;beamline;Biological Sciences;Biophysics;Collaborations;Communities;Crystallography;design and construction;Equipment;Funding;Funding Agency;Future;Generations;Grant;Institution;instrumentation;International;Laboratories;laboratory facility;Light;Maintenance;National Center for Research Resources;National Institute of Biomedical Imaging and Bioengineering;novel;operation;Outcome;Peer Review;Photons;Productivity;programs;public health relevance;ranpirnase;Research;Roentgen Rays;Secure;Source;structural biology;Synchrotrons;Technology;Training;Training Programs;Training Support;United States National Institutes of Health;Universities;X ray spectroscopy","PROJECT_TITLE":"Case Center for Synchrotron Bioscience","SERIAL_NUMBER":"9998","STUDY_SECTION":"ZEB1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"S1","SUPPORT_YEAR":"6","TOTAL_COST":"37800","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8781972","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant):  RAP as a therapeutic compound for neuronal regeneration after spinal cord injury Novoron Bioscience Inc. RESEARCH &RELATED Other Project Information 7. Project Summary There are an estimated 12,000 to 20,000 new cases of spinal cord injury (SCI) each year and 1.28 million people in the United States are paralyzed in some form due to SCI. Currently, there are no clinically available treatments that target the degraded myelin, one of the causes of regenerative failure in the central nervous system (CNS) after SCI. LRP1 was recently identified as a novel receptor of myelin-associated inhibitors (MAIs), the components of degraded myelin responsible for regenerative failure. We have shown in vivo that infusion of the LRP1 antagonist RAP into the injured spinal cord results in attenuation of RhoA, the critical neuronal signal involved in extrinsically-mediated regenerative failure. Direct inhibition of RhoA has been shown to enhance neuronal regeneration after SCI in rodent models and a pan-Rho inhibitor has shown evidence of efficacy in humans in exploratory clinical trials. However, current therapeutics have so far been limited to single dose administration. In contrast, RAP has been demonstrated to be readily available to the CNS from the peripheral circulation therefore making it amenable to repeated administration over time giving it therapeutic advantages over current pan-RhoA inhibitors. As beneficial results have already been observed using direct infusion to the injury site, we first wish to assess whether peripheral administration of RAP has comparable beneficial effects on the signaling events associated with regenerative failure after SCI. To accomplish this, an intravenous administration protocol capable of resulting in sufficient levels of RAP in the CNS must first be established. We will then perform long term studies (8-week injury course) to assess histological regeneration of damaged neurons, as well as evaluate the behavioral benefits over time such as improved locomotion, increased paw utilization, and response to external stimuli in affected extremities. We will also evaluate the effects of RAP infusion on immune infiltration and lesion formation. As LRP1 has been shown to be a critical facilitator of myelin mediated neuroregenerative failure, we hypothesize that therapeutic application of RAP to block the LRP1/MAI interaction will result in significant neuronal regeneration after SCI. Additionally, the unique biological characteristics of RAP such as CNS bioavailability could make it a superior, or perhaps combinatorial, therapeutic approach to the current pan-RhoA inhibitors. As such, RAP appears to be a high-value potential therapeutic for restoring function after acute spinal cord injury. This technology s protected by US patent pending (US2012/035125), which is currently in process of exclusive license to Novoron Inc. from the University of California San Diego.        ","ACTIVITY":"R41","ADMINISTERING_IC":"NS","APPLICATION_TYPE":"1","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"06/27/2014","BUDGET_START":"07/01/2014","BUDGET_END":"06/30/2015","CFDA_CODE":"853","CORE_PROJECT_NUM":"R41NS086197","ED_INST_TYPE":"","FOA_NUMBER":"PA-13-235","FULL_PROJECT_NUM":"1R41NS086197-01A1","FUNDING_ICs":"NINDS:224952\\","FUNDING_MECHANISM":"SBIR-STTR","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE","NIH_SPENDING_CATS":"","ORG_CITY":"LA JOLLA","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"52","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"NOVORON BIOSCIENCE, INC.","ORG_STATE":"CA","ORG_ZIPCODE":"920371454","PHR":"PUBLIC HEALTH RELEVANCE:  RAP as a therapeutic compound for neuronal regeneration after spinal cord injury Novoron Bioscience Inc. RESEARCH &RELATED Other Project Information 8. Project Narrative There are approximately 12-20,000 new cases of spinal cord injury (SCI) each year in the United States, and there are no clinically available treatments capable of restoring the regenerative capacity of neurons in the central nervous system after injury. We have shown that LRP1 is a novel receptor mediating extrinsic neuroregenerative failure, and blocking LRP1 in the injured spinal cord with the LRP1 antagonist receptor associated protein (RAP) results in attenuation of the neuronal signaling that leads to regenerative arrest. The goal of this work is to further assess the viability of RAP as a biologica compound capable of restoring function and quality of life for patients suffering from SCI and complete the proof of concept work necessary for a phase II application and future pre-clinical work needed for IND application.                ","PI_IDS":"6618568;11517660 (contact);","PI_NAMEs":"LEE, JAE K;STILES, TRAVIS LEE (contact);","PROGRAM_OFFICER_NAME":"FERTIG, STEPHANIE ","PROJECT_START":"07/01/2014","PROJECT_END":"06/30/2015","PROJECT_TERMS":"Acute;Affect;Animal Model;Attenuated;attenuation;axon growth;axon regeneration;Behavioral;Behavioral Assay;Binding (Molecular Function);Biologic Characteristic;Biological Availability;Blood - brain barrier anatomy;Blood Circulation;California;Chest;Cicatrix;Clinical Trials;clinically relevant;combinatorial;comparative efficacy;Dose;Drug Design;Event;Failure (biologic function);functional restoration;Future;Generations;Goals;Human;Immune;improved;in vivo;Infiltration;Inflammation;Infusion procedures;inhibitor/antagonist;Injury;Intravenous;intravenous administration;intravenous injection;Investigational Drugs;LDL-Receptor Related Proteins;Lead;Legal patent;Lesion;Licensing;Ligand Binding;Limb structure;Locomotion;Longitudinal Studies;Mediating;Methods;Methylprednisolone;Mission;Modeling;Molecular Chaperones;Monomeric GTP-Binding Proteins;Myelin;Natural regeneration;Nerve Regeneration;Neuraxis;Neurons;Neuroprotective Agents;novel;Outcome;Paralysed;Pathology;Pathway interactions;Patients;Peripheral;Peripheral Nervous System;Pharmaceutical Preparations;Phase;Physicians;pre-clinical;Process;Property;Proteins;Protocols documentation;public health relevance;Quality of life;receptor;regenerative;Research;response;restoration;rho;Rodent;Rodent Model;scavenger receptor;Signal Pathway;Signal Transduction;Site;Spinal Cord;Spinal cord injury;Stimulus;Technology;Testing;Therapeutic;Therapeutic Effect;Therapeutic Uses;Time;Tissues;Transferase;Treatment Efficacy;United States;Universities;Work","PROJECT_TITLE":"RAP as a therapeutic compound for neuronal regeneration after spinal cord injury","SERIAL_NUMBER":"86197","STUDY_SECTION":"ZRG1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"A1","SUPPORT_YEAR":"1","TOTAL_COST":"224952","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8636501","ABSTRACT_TEXT":"   DESCRIPTION (provided by applicant): Understanding the mechanisms that control inflammation in the CNS is critical to finding therapies for limiting damage to the brain from pathogens or neurodegenerative disease. Yet our knowledge is primarily limited to the adhesion molecules that facilitate entry to this site and not the factors that influence inflammatory cells once within the brain. Infection with the protozoan parasite Toxoplasma gondii leads to a chronic infection in the CNS with a continuous inflammatory response required in the brain to maintain latency. The absence of an appropriate immune response leads to the development of Toxoplasmic encephalitis (TE) and is therefore a common cause of AIDS related fatalities. Toxoplasma is an extremely common human infection, yet, in the immune- competent host there is no apparent pathology related to continuous inflammation in the brain. Thus, T. gondii infection leads to an immune response in the brain robust enough to provide protection against the parasite but sufficiently controlled to prevent immunopathology. A hypothesis being examined in our lab is that during chronic infection, cell migration can be guided in the brain by chemokine networks thereby controlling infection and limiting tissue damage. Recent studies of ours have demonstrated that following Toxoplasma infection, the presence of a reticular network is formed on which T cells migrate within the parenchyma of the brain. In addition, the chemokines CCL19 and CCL21 are significantly upregulated with cables of CCL21 associated with migrating T cells. These chemokines, known for their role in T cell and dendritic cell migration in the periphery, have not been well studied in the context of migration within the CNS. Experiments will be conducted to test the hypothesis that increased expression of CCL19/CCL21 in the infected brain is a mechanism to guide leukocytes within the brain parenchyma to control infection. Understanding how peripheral cells are directed to the site of infection and still prevent immunopathology in the CNS has direct relevance to controlling the multiple infectious pathogens that affect the brain. In addition, it may also lead to novel mechanisms to manipulate a pathological or deficient immune response in the CNS.      ","ACTIVITY":"R01","ADMINISTERING_IC":"NS","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"04/18/2014","BUDGET_START":"04/01/2014","BUDGET_END":"03/31/2015","CFDA_CODE":"853","CORE_PROJECT_NUM":"R01NS072298","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"PA-10-067","FULL_PROJECT_NUM":"5R01NS072298-04","FUNDING_ICs":"NINDS:329176\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE","NIH_SPENDING_CATS":"","ORG_CITY":"RIVERSIDE","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"NONE","ORG_DISTRICT":"41","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF CALIFORNIA RIVERSIDE","ORG_STATE":"CA","ORG_ZIPCODE":"925210001","PHR":" This proposal investigates the regulation of the inflammatory response in the brain during Toxoplasma infection. This is one of the most common Human pathogens however, in the absence of an appropriate Immune response can lead to fatal encephalitis. Understanding immune regulation in the brain during Toxoplasma infection, in addition to controlling infection in the brain, may provide novel mechanisms to counter inflammation that is prevalent during neurodegenerative diseases.            ","PI_IDS":"9772405;","PI_NAMEs":"WILSON, EMMA HARRIET;","PROGRAM_OFFICER_NAME":"WONG, MAY ","PROJECT_START":"09/01/2011","PROJECT_END":"03/31/2016","PROJECT_TERMS":"Acquired Immunodeficiency Syndrome;Address;Affect;Astrocytes;Binding (Molecular Function);Biological Assay;Brain;CCL19 gene;CCL21 gene;CD4 Positive T Lymphocytes;Cell Adhesion Molecules;cell motility;Cells;chemokine;chemokine receptor;Chemotaxis;Chronic;Collagen;Data;Dendritic Cells;Development;Diffuse;Effector Cell;Encephalitis;Equilibrium;Flow Cytometry;Generations;Glial Fibrillary Acidic Protein;Human;Immune;Immune response;Immunohistochemistry;immunopathology;improved;in vivo;Infection;Infection Control;Inflammation;Inflammatory;Inflammatory Response;Knowledge;Lead;Leukocytes;Measures;Memory;Microarray Analysis;migration;Mus;Neurodegenerative Disorders;Neuroglia;novel;overexpression;Parasite Control;Parasites;pathogen;Pathology;Peripheral;Phenotype;Population;prevent;Principal Investigator;Production;programs;Publishing;Regulation;Regulatory T-Lymphocyte;research study;response;Reverse Transcriptase Polymerase Chain Reaction;Role;Signal Transduction;Site;Slice;Source;Spottings;T-Lymphocyte;Technology;Testing;Time;Tissues;Toxoplasma;Toxoplasma gondii;Toxoplasmosis;Up-Regulation (Physiology)","PROJECT_TITLE":"Cell Migration in the Infected Brain","SERIAL_NUMBER":"72298","STUDY_SECTION":"PTHE","STUDY_SECTION_NAME":"Pathogenic Eukaryotes Study Section","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"4","TOTAL_COST":"329176","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8846753","ABSTRACT_TEXT":"This application is for an ICTSA to be established at the University of Texas Medical Branch at Galveston (UTMB). Our rationale is that UTMB brings depth to the CTSA consortium, because: we are the only academic health center with both an NIAID-funded Regional Center for Excellence in Biodefense and a National Biocontainment Laboratory;we are the only center with two NIH-funded translationally oriented proteomics centers in biomarker research;we have developed translational research programs with three national laboratories (the Galveston and Sandia National Laboratories and NASA);we have trained more underrepresented minority MDs than any non-historically Black institution in the US;we have the only approved PhD-awarding Clinical Science Training program in a public university in Texas;and we have the largest telemedicine operation in the world. In response to Hurricane Ike, we have established a richer outpatient clinical research network in South East Texas. Our ICTSA are to: 1. Facilitate translational research as a rigorous discipline;2. Develop translational research training programs at all levels in the graduate continuum;3. Effectively conduct and bridge step 1 translational research (Tl) to steps 2 (T2) and -3 (T3);and 4. Interface productively with the national CTSA Consortium. To accomplish these goals, we have organized our ICTSA into 12 \"Key Resources\" ~ combinations of university core laboratories and intellectual resources, integrated by a single point of investigator/trainee contact. This structure will make us more rapidly responsive to the needs of our investigators and trainees. In this application, our Key Resources are assembled to support the translational goals of exemplar multidisciplinary translational teams (MTTs), generally organized around our successful NIH- funded interdisciplinary research centers. Three overiying principles will guide our ICTSA's operations, to: 1. Employ proactive mechanisms in identifying new team-oriented research opportunities;2. Prioritize trainee involvement in a team-based culture;and 3. Integrate systems biological approaches into translational research. UTMB's senior leadership is providing significant new institutional resources, including establishing the Institute for Translational Sciences (ITS), our new home for translational research;new commitments of pilot grant support; administrative support;and support for a significant expansion of bioinformatics faculty. The ITS Director reports directly to UTMB's Provost, who is responsible for integration of research and education university-wide. We are thus well-positioned to achieve our goals, significantly transform clinical and translational research at UTMB, and contribute to the national CTSA Consortium. RELEVANCE (See instructions): The ICTSA will allow our researchers to more quickly and effectively translate basic science discoveries into improvements in human health. In particular this award will allow us to build teams of researchers with diverse skills who can work effectively towards a health outcome-related goal. In this way the ICTSA will break down communication, technology and regulatory barriers and transform how our university conducts patient-oriented research.","ACTIVITY":"KL2","ADMINISTERING_IC":"TR","APPLICATION_TYPE":"3","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"05/16/2014","BUDGET_START":"05/16/2014","BUDGET_END":"03/31/2015","CFDA_CODE":"350","CORE_PROJECT_NUM":"KL2TR000072","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"RFA-RM-08-002","FULL_PROJECT_NUM":"3KL2TR000072-05S1","FUNDING_ICs":"NCATS:42337\\","FUNDING_MECHANISM":"Other Research Related","FY":"2014","IC_NAME":"NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES","NIH_SPENDING_CATS":"","ORG_CITY":"GALVESTON","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"INTERNAL MEDICINE/MEDICINE","ORG_DISTRICT":"","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF TEXAS MEDICAL BR GALVESTON","ORG_STATE":"TX","ORG_ZIPCODE":"775555302","PHR":"","PI_IDS":"1882736;","PI_NAMEs":"BRASIER, ALLAN R.;","PROGRAM_OFFICER_NAME":"WILDE, DAVID B.","PROJECT_START":"07/14/2009","PROJECT_END":"03/31/2015","PROJECT_TERMS":"Award;base;Basic Science;biodefense;Bioinformatics;Biological Markers;biological systems;Clinical Research;Clinical Sciences;Communication;Discipline;Doctor of Philosophy;Educational aspects;Faculty;Funding;Goals;Grant;Health;Home environment;Human;Hurricane;Institutes;Institution;Instruction;Interdisciplinary Study;Laboratories;Leadership;Medical;multidisciplinary;National Institute of Allergy and Infectious Disease;operation;Outcome;Outpatients;patient oriented research;Positioning Attribute;programs;Proteomics;Reporting;Research;Research Personnel;Research Training;Resources;response;skills;Structure;Technology;Telemedicine;Texas;Training;Training Programs;Translating;Translational Research;Underrepresented Minority;United States National Aeronautics and Space Administration;United States National Institutes of Health;Universities;Work","PROJECT_TITLE":"UTMB Clinical and Translational Science Award","SERIAL_NUMBER":"72","STUDY_SECTION":"ZRR1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"S1","SUPPORT_YEAR":"5","TOTAL_COST":"42337","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8775460","ABSTRACT_TEXT":"DESCRIPTION (provided by applicant): Sarcopenia, defined as age related loss of muscle mass and muscle function and strength, is very prevalent among the elderly. Sarcopenia is one of the largest public health problems facing a rapidly increasing, aging population in the United States and leads to increased incidence of falls, fractures and associated morbidities. Previous observations from our laboratory, as well as from many other laboratories, have demonstrated the efficacy of 2-hydroxy-2-methylbutyrate (HMB) alone or in combination with other amino acids in enhancing muscle strength and function in young athletes. We have recently demonstrated that the combination of HMB with two other amino acids, arginine and lysine, was effective in increasing muscle mass in elderly men and women during a year-long prospective study. When analyzing the data (Preliminary Results), we demonstrated a close correlation between the levels of 25-OH Vitamin D3 in this population and the level of improvement in muscle strength. We noted that individuals with plasma 25-OH Vitamin D3 levels >30 ng/ml manifested muscle strength gains supplemented with HMB and two amino acids, while those with plasma 25- OH Vitamin D3 of <30 ng/ml did not. These data form the basis of our current hypothesis that the combination of HMB and Vitamin D supplementation will be synergistic and will result in significant enhancements in overall muscle strength, function and muscle mass. We propose these Phase I and Phase II studies to prove our hypothesis. The Phase I study will test the short-term (12-wk) efficacy of a combination of HMB and Vitamin D to prevent and reverse muscle sarcopenia and the associated losses of muscular strength and functionality in older adults. We plan to recruit 100 men and women who will be assigned to one of four dietary treatments: (1) Control;(2) HMB (calcium salt), 3.0 g/day;(3) 2,000 IU Vitamin D;and (4) HMB, 3.0 g/d + 2,000 IU Vitamin D. The subjects will undergo a 3-day per week exercise program, and body composition and strength will be measured at four week intervals. We expect to demonstrate the synergy between HMB and Vitamin D in this short study. Phase II will test the long-term (12-mos) efficacy of this synergistic combination of HMB and Vitamin D on the enhancement of muscle strength and functionality in the elderly, thus leading to improved quality of life. Phase II will include an exercise arm just like Phase I, but will also include a non-exercise arm because many elderly adults do not participate in an exercise program. In addition to body composition and function and strength data, muscle biopsies will be obtained and muscle fiber and proteomic analysis will be performed. We anticipate that the data generated will lead to further research looking at mechanism(s) involved in loss of muscle and muscle function in the elderly. Improvement in muscle strength and muscle function as well as improvements in body composition over the year-long study will be used to market a product containing HMB and Vitamin D.      ","ACTIVITY":"R44","ADMINISTERING_IC":"AG","APPLICATION_TYPE":"4","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"03/12/2014","BUDGET_START":"03/15/2014","BUDGET_END":"02/28/2015","CFDA_CODE":"866","CORE_PROJECT_NUM":"R44AG034722","ED_INST_TYPE":"","FOA_NUMBER":"PA-09-080","FULL_PROJECT_NUM":"4R44AG034722-02","FUNDING_ICs":"NIA:374999\\","FUNDING_MECHANISM":"SBIR-STTR","FY":"2014","IC_NAME":"NATIONAL INSTITUTE ON AGING","NIH_SPENDING_CATS":"","ORG_CITY":"AMES","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"04","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"METABOLIC TECHNOLOGIES, INC.","ORG_STATE":"IA","ORG_ZIPCODE":"500108656","PHR":"Current estimates place a large portion of the older U.S. populous at risk for falls with potential morbidities. A large percentage of these falls are directly related to decreased muscle strength and function. Since a significant portion of the older population is at risk of having a Vitamin D deficiency, a product that corrects such deficiencies and specifically targets muscle strength, function, and mass is likely to produce significant improvements in health, improve the quality of life, and in particular, help to decrease the incidence of falls and injury in this group. Moreover, based upon the incidence of widespread Vitamin D deficiency in all ages, we anticipate the younger population will also benefit from similar supplementation.","PI_IDS":"8837563;","PI_NAMEs":"RATHMACHER, JOHN A;","PROGRAM_OFFICER_NAME":"HANNAH, JUDY S.","PROJECT_START":"07/01/2010","PROJECT_END":"02/28/2016","PROJECT_TERMS":"Adult;Affect;Age;age related;Aging;aging population;American;Amino Acids;arginyllysine;arm;Arthritis;Back;base;Biochemical;Biopsy;Body Composition;bone;Bone callus;Bone Density;Bone remodeling;bone turnover;Bunion;Calcium;Caliber;Censuses;Centers for Disease Control and Prevention (U.S.);Cholecalciferol;Climate;clinically significant;combat;Communicable Diseases;Data;Data Analyses;Deformity;Diet;Dietary Intervention;Disease;disorder prevention;economic cost;Economics;Effectiveness;Elderly;Elderly man;Elderly woman;Equilibrium;Exercise;Experimental Designs;Fall prevention;fall risk;falls;Fast-Twitch Muscle Fibers;Fiber;Flexor;foot;Fracture;Functional disorder;Future;Gait;General Population;grasp;Health;improved;Incidence;Individual;Injury;Investigation;Joint Instability;Knee;Knowledge;Laboratories;Labyrinth;Lead;Legal patent;Life;Literature;Longitudinal Studies;Marketing;Measurement;Measures;men;Metabolic;metabolic abnormality assessment;Morbidity - disease rate;Muscle;muscle aging;Muscle Fibers;muscle form;Muscle function;muscle metabolism;muscle strength;Musculoskeletal;Nutrient;Older Population;Pharmaceutical Preparations;Phase;phase 1 study;phase 2 study;Phase I Clinical Trials;Plasma;Pneumonia;Population;prevent;Probability;programs;prospective;Prospective Studies;protein degradation;Proteomics;public health medicine (field);Publishing;Quality of life;Recruitment Activity;Relative (related person);Reporting;Research;Risk;Risk Factors;sarcopenia;screening;Sodium Chloride;Somatotype;sports related nutrition;Structure of nail of toe;Sum;Supplementation;Techniques;Testing;Time;Time Study;Toes;Training;Translating;United States;Vision;Vitamin D;Vitamin D Deficiency;Vitamin D2;wasting;Woman","PROJECT_TITLE":"Nutritional Intervention for Age-Related Muscular Function and Strength Losses","SERIAL_NUMBER":"34722","STUDY_SECTION":"ZRG1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"2","TOTAL_COST":"374999","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8704868","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): Approximately 37,000 people die in the U.S. each year just due to seasonal influenza outbreaks. Efforts to match each year's batch of prevailing influenza viruses fail to predict the strains that will spread in the U.S. 23% of the time. The influenza season of 2007-2008 was one example of the mismatch between prediction and actual strain prevalence. In that season, two of the three influenza strains were mismatched with the viruses that spread in the population leading to influenza infections in vaccinated individuals Therefore, year to year seasonal influenza antigen prediction is not optimal. Beyond seasonal influenza, more troubling is that it is impossible to predict the next pandemic strain of influenza despite our greatest attempts to monitor new out breaks. Even if the strain could be determined at the onset of the pandemic, the time needed to develop and produce an effective vaccine for world-wide distribution may take too long to provide a protective vaccine to the world population. We propose to create and test \"centralized\" influenza genes for the production of prophylactic cross-reactive immunity to combat both seasonal and pandemic influenza. Centralized antigens are antigens that have been computationally engineered to represent common or primordial antigen sequences shared by many or all current viral antigen variants. The advantage of using a centralized antigen is that the genetic distance from the vaccine strain to the challenge strain is half of that of a random antigen and a challenge strain. Therefore, unlike selected wildtype candidate antigens, centralized antigens have substantially higher general homology to all strains of influenza, increasing their ability to drive cross-reactive immune responses to control influenza variants. The specific aims of this study are 1) to create reassorted influenza viruses expressing centralized genes. These will include hemagglutinin (HA) and neuraminidase (NA) for H1, H2, H3, H5, N1 and N2 subtypes. The centralized viruses (H1N1-con, H2N2-con, H3N2-con, and H5N1-con) will be used to make traditional inactivated vaccines. 2) In order to determine the most broadly protective vaccine, mice will be immunized with centralized and wildtype inactivated vaccines. The immunized mice will be challenged with divergent influenza viruses and the best vaccine will be determined by the ability to induce the broadest levels of protection. 3) The final goal of the study is to determine the effects of using a centralized influenza vaccine in the context of prior anti-influenza immunity. Vaccine safety is paramount and these studies will determine if boosting with centralized vaccines results in original antigeni sin and dominant non-neutralizing immune responses. A final analysis will be done in ferrets, since ferrets more closely resemble natural influenza infection in humans. The overall goal of this project is to determine if a centralized vaccine is capable of inducing cross-protective immunity against influenza virus with greater breadth than that of a traditional influenza antigen. The most broadly protective antigens, whether centralized or wildtype, could be used as a first line defense or backup vaccine against pandemic or \"weaponized\" influenza viruses in the case of vaccine mismatch or could be incorporated into the annual vaccine formulation.        ","ACTIVITY":"R01","ADMINISTERING_IC":"AI","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"06/11/2014","BUDGET_START":"08/01/2014","BUDGET_END":"07/31/2015","CFDA_CODE":"855","CORE_PROJECT_NUM":"R01AI097241","ED_INST_TYPE":"","FOA_NUMBER":"PA-11-260","FULL_PROJECT_NUM":"5R01AI097241-03","FUNDING_ICs":"NIAID:400826\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES","NIH_SPENDING_CATS":"","ORG_CITY":"ROCHESTER","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"01","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"MAYO CLINIC ROCHESTER","ORG_STATE":"MN","ORG_ZIPCODE":"559050001","PHR":" It is impossible to create a perfect vaccine year after year. In fact, every year there is a greater than 1 in 5 chance that the vaccine will be a mismatch. The risk of vaccine mismatch is amplified exponentially in the event of a global pandemic with virus such as the H5 avian or bird flu virus. Since, we cannot predict with 100% certainty what the circulating virus will be every year;we propose to create centralized influenza virus genes that most closely resemble all influenza virus genes within a subtype. We believe these genes will provide superior cross-protective immunity in the case of a vaccine mismatch.            ","PI_IDS":"7523603;","PI_NAMEs":"WEAVER, ERIC A.;","PROGRAM_OFFICER_NAME":"SALOMON, RACHELLE ","PROJECT_START":"08/10/2012","PROJECT_END":"07/31/2016","PROJECT_TERMS":"Address;anti-influenza;Antigens;Avian Influenza A Virus;base;Birds;combat;Data;Disease Outbreaks;Drug Formulations;egg;Engineering;Event;Ferrets;Foundations;Genes;Genetic;Goals;H1N1 vaccine;Harvest;Hemagglutinin;Human;Immune response;Immunity;Inactivated Vaccines;Individual;Infection;Influenza;Influenza A Virus, H1N1 Subtype;Influenza A Virus, H5N1 Subtype;influenza outbreak;influenza virus gene;Influenza virus vaccine;influenzavirus;Liquid substance;Monitor;mouse model;Mus;Neuraminidase;pandemic disease;pandemic influenza;Plasmids;Population;Prevalence;Production;prophylactic;Recombinants;Research;Risk;safety study;seasonal influenza;Seasons;Solutions;System;Testing;Time;translational study;Vaccinated;vaccine safety;Vaccines;Variant;Viral Antigens;Virus","PROJECT_TITLE":"Foundation Immunogens for Influenza Vaccines","SERIAL_NUMBER":"97241","STUDY_SECTION":"VMD","STUDY_SECTION_NAME":"Vaccines Against Microbial Diseases Study Section","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"3","TOTAL_COST":"400826","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8728483","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): Papillary thyroid cancer (PTC) typically has a favorable prognosis;however, patients with PTC carrying the BRAFV600E mutation show resistance to radioiodine treatment and have high rates of metastases and low survival rates. Inhibitors of BRAFV600E, including vemurafenib, have been tested recently as treatments for BRAFV600E-melanomas, with very promising results. However, development of secondary tumor resistance to these compounds has been reported. Another potential player in PTC aggressiveness is vascular endothelial growth factor receptor 2 (VEGFR2), a crucial regulator of angiogenesis. Sorafenib, which targets VEGFR2, was only partially effective against metastatic PTC, suggesting secondary resistance mechanisms to this drug as well. Our preliminary results show that metastatic primary human BRAFV600E positive PTC cells in vitro were resistant to high doses of either vemurafenib or sorafenib alone, but combined treatment with both drugs decreased cell viability by greater than 90%. BRAFV600E up-regulates VEGFR2 and pERK1/2 in PTC cells, triggering recruitment of endothelial cells and pericytes. We also observed upregulation of ACAC[unreadable] (metabolic gene) suggesting that BRAFV600E harnesses a metabolic response that promotes PTC metastasis, a novel mechanism. Our preliminary data also indicate that VEGFR2 is associated with neck recurrence in BRAFV600E PTC. Our objective is to determine how BRAFV600E and VEGFR2 fit into the autocrine and paracrine signaling pathways that control PTC cell progression. Our central hypothesis is that BRAFV600E and VEGFR2 pathways synergize in PTC cells, increasing secretion of extracellular matrix (ECM) proteins and leading to increased PTC cell adhesion, migration/invasion, and angiogenesis. We propose a secondary pathway in which the BRAFV600E/ERK1/2 signaling cascade triggers hyper-expression of VEGFR2 in PTC cells. The alternate VEGFR2 pathway synergizes with residual BRAFV600E activity in the presence of vemurafenib, conferring secondary drug resistance in PTC cells. We will test this by manipulating VEGFR2 and BRAFV600E function and assessing tumorogenic properties in our novel models: a 3D co-culture system that recapitulates the PTC microenvironment, an orthotopic mouse with primary human PTC cells with heterozygous BRAFWT/V600E, and ChIp-seq analysis. Aim 1: To elucidate the autocrine and paracrine pathways by which BRAFV600E and VEGFR2 promote PTC aggressiveness. These studies will delineate VEGFR2-interacting ECM proteins that enhance ERK1/2 phosphorylation in BRAFV600E PTC and provide new insight into vemurafenib and sorafenib secondary drug resistance. Aim 2: To assess whether VEGFR2 protein expression is a long-term prognostic biomarker for PTC aggressiveness in BRAFV600E PTC. Aim 3: To assess efficacy of anti-BRAFV600E and anti-VEGFR2 combined therapy in a pre-clinical mouse model of human heterozygous BRAFWT/V600E PTC. These proposed studies are highly likely to provide evidence supporting clinical trials of combined targeted therapy for BRAFV600E-PTC and identify novel targets for drug development and biomarkers for aggressive PTC.        ","ACTIVITY":"R01","ADMINISTERING_IC":"CA","APPLICATION_TYPE":"1","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"05/29/2014","BUDGET_START":"07/01/2014","BUDGET_END":"05/31/2015","CFDA_CODE":"394","CORE_PROJECT_NUM":"R01CA181183","ED_INST_TYPE":"","FOA_NUMBER":"PA-13-302","FULL_PROJECT_NUM":"1R01CA181183-01A1","FUNDING_ICs":"NCI:361050\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL CANCER INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"BOSTON","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"08","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"BETH ISRAEL DEACONESS MEDICAL CENTER","ORG_STATE":"MA","ORG_ZIPCODE":"02215","PHR":"PUBLIC HEALTH RELEVANCE: Although most papillary thyroid cancers (PTC) respond well to treatment and have excellent prognosis, BRAFV600E positive metastatic PTC are resistant to current treatments and correlate with mortality;therefore, early diagnosis and new therapies are needed. Recent research provides clues to understanding PTC aggressiveness and secondary drug resistance to therapies targeting BRAFV600E or vascular endothelial growth factor receptor 2 (VEGFR2) in BRAFV600E-positive metastatic PTC. Results from this study will identify novel biomarkers and drug development targets for BRAFV600E metastatic PTC refractory to current treatments and provide preclinical evidence for the efficacy of combined drug therapy targeting BRAFV600E and VEGFR2.            ","PI_IDS":"10536209;","PI_NAMEs":"NUCERA, CARMELO;","PROGRAM_OFFICER_NAME":"SORG, BRIAN S","PROJECT_START":"07/01/2014","PROJECT_END":"05/31/2019","PROJECT_TERMS":"Acetyl-CoA Carboxylase;anaplastic thyroid cancer;angiogenesis;autocrine;Autocrine Communication;Automobile Driving;base;BAY 54-9085;Biological Markers;cancer cell;cancer therapy;Cell Adhesion;cell motility;Cell Survival;Cell-Cell Adhesion;Cells;Chip seq;Clinical Trials;Coculture Techniques;Collagen;Combined Modality Therapy;Data;density;Development;Dose;drug development;Drug resistance;Early Diagnosis;Endothelial Cells;Extracellular Matrix;Extracellular Matrix Proteins;Genes;Goals;Human;Implant;improved;In Vitro;in vitro Assay;inhibitor/antagonist;insight;Integrins;Link;Luciferases;lymph nodes;Malignant neoplasm of lung;MAPK3 gene;melanoma;Metabolic;Metabolism;migration;Modeling;Mortality Vital Statistics;mouse model;Mus;Mutation;Neck;Neoplasm Metastasis;novel;Oral;outcome forecast;Papillary thyroid carcinoma;paracrine;Paracrine Communication;Pathway interactions;Patients;Pericytes;Pharmaceutical Preparations;Pharmacotherapy;Phosphorylation;Phosphotransferases;Play;pre-clinical;Process;Prognostic Marker;Property;protein expression;Proteins;Proteomics;public health relevance;receptor;Recurrence;Refractory;Reporting;Research;Residual state;Residual Tumors;Resistance;resistance mechanism;response;Role;Sampling;SCID Mice;screening;Signal Pathway;Signal Transduction;small hairpin RNA;Specimen;standard care;Survival Rate;System;Testing;therapy resistant;Thyroid Gland;Transcription factor genes;Treatment Efficacy;tumor;tumor growth;tumor microenvironment;tumor progression;Up-Regulation (Physiology);Vascular Endothelial Growth Factor A;Vascular Endothelial Growth Factor Receptor-2","PROJECT_TITLE":"BRAFV600E and VEGFR2 synergize to trigger papillary thyroid cancer progression","SERIAL_NUMBER":"181183","STUDY_SECTION":"MCE","STUDY_SECTION_NAME":"Molecular and Cellular Endocrinology Study Section","SUBPROJECT_ID":"","SUFFIX":"A1","SUPPORT_YEAR":"1","TOTAL_COST":"361050","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8627569","ABSTRACT_TEXT":"ABSTRACT: Novel adoptive T cell therapies have enabled long lasting objective clinical responses in a significant proportion of patients with metastatic melanoma. Treatment efficacy and availability could be further improved by ex vivo genetic modification of lymphocytes allowing generation of large numbers of cells with enhanced anti-tumor function. The development of such adoptive cell transfer immune therapies is critically dependent on the availability of tools to track the distribution of genetically modified lymphocytes following transplantation in melanoma patients. Work by Program Project Grant (PPG) Investigators in animal models of cancer and in humans has demonstrated that this goal could be accomplished using novel molecular imaging techniques such as Positron Emission Tomography (PET).  To visualize the distribution of genetically modified T lymphocytes and Hematopoietic Stem Cells transplanted in melanoma patients, these cells will be engineered to express a PET reporter gene derived from the Herpes Simplex Virus 1 thymidine kinase (HSVI-tk). HSVI-tk has been used extensively in clinical trials as a \"suicide gene\" and has a very high affinity for the PET probe (9-[4-[(18)F]fluoro-3-(hydroxymethyl)-butyl]guanine) (9(18)'F]FHBG). [9(18)F]FHBG administered in trace amounts accumulates specifically in cells expressing HSVI-tk and resulting signals can be detected by PET. We will use this technique for in vivo \"counting\" of genetically  modified cells at various sites throughout the body, including lymphoid organs and metastatic melanoma  deposits. Such measurements cannot be performed using conventional technologies and could provide eariy  prediction markers for therapeutic responses.  To support imaging studies by PPG Investigators, we propose to establish a Biological Imaging Core for noninvasive  monitoring of immune responses. This Core will complement state-of-the-art 'in vitro'immUne  monitoring measurements described in Core A and will enable PPG Investigators to pertorm preclinical and  clinical 'in vivo'immune monitoring studies using multiple imaging modalities.  The proposed Core will take advantage of the unique expertise and infrastructure for functional and anatomical  tomographic imaging already available at UCLA and will also coordinate preclinical imaging experiments  performed at other participating institutions. We envision that the Imaging Core will help cement long-term  interactive multi-institutional collaborations involving experts in imaging, gene therapy, basic and clinical  immunology, who are at the forefront of cancer immunotherapy transitional research.","ACTIVITY":"P01","ADMINISTERING_IC":"CA","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"05/23/2014","BUDGET_START":"03/01/2014","BUDGET_END":"02/28/2015","CFDA_CODE":"","CORE_PROJECT_NUM":"P01CA132681","ED_INST_TYPE":"","FOA_NUMBER":"","FULL_PROJECT_NUM":"5P01CA132681-05","FUNDING_ICs":"NCI:360372\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL CANCER INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"PASADENA","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"29","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"CALIFORNIA INSTITUTE OF TECHNOLOGY","ORG_STATE":"CA","ORG_ZIPCODE":"900952000","PHR":"","PI_IDS":"1859339;","PI_NAMEs":"CZERNIN, JOHANNES;","PROGRAM_OFFICER_NAME":"","PROJECT_START":"","PROJECT_END":"","PROJECT_TERMS":"","PROJECT_TITLE":"Biological Imaging Core","SERIAL_NUMBER":"132681","STUDY_SECTION":"ZCA1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"7258","SUFFIX":"","SUPPORT_YEAR":"5","TOTAL_COST":"","TOTAL_COST_SUB_PROJECT":"360372"}
{"APPLICATION_ID":"8593995","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant):     The goal of the proposed study is to develop and test an adjunctive intervention (CLASP) to reduce suicide behavior and re-hospitalization in military veterans hospitalized for suicidal behavior. Suicide is one of the leading causes of death for military personnel and for the first time in recorded history the rates of military suicides are exceeding civilian rates. Despite the public and patient health costs associated with suicidal ideation and behavior, existing efforts have not appreciably reduced the rates of suicidal behavior in the military. Consequently, finding novel, efficacious, and acceptable methods to reduce suicide behaviors is of great military health relevance and should be a fundamental goal of clinical research with military veterans. The Coping Long Term with Active Suicide Program (CLASP) is an adjunctive intervention that combines aspects of problem-solving therapy, case-management, family support, and assessment. The program is a 6- month, adjunctive, telephone-based program designed for patients hospitalized for suicide behavior. CLASP includes, 3 individual sessions and one family session conducted while a patient is in the hospital, and a series of phone calls to both the patient and an identified significant other over the course of 6-months post- discharge. The program is designed to be easily integrated into the VA's current system, can be delivered by master's level clinicians, and will expand on, and compliment the role of the National Suicide Coordinator.  The primary objective of this study is to test the efficacy of CLASP in a sample of veterans hospitalized for suicide behavior. Two hundred veterans will be randomly assigned to either the CLASP intervention or to a Safety Assessment and Follow-up Evaluation (SAFE) control condition. Both programs will be delivered as adjuncts to treatment as usual. Participants will be assessed at the end of the active intervention phase (3 and 6 months post-discharge from hospital) and again at 9 and 12 months post discharge. Efficacy of the program will be determined by several primary outcomes including number of attempts, number of re-hospitalizations, severity and chronicity of suicidal ideation. Secondary analyses will be conducted to help identify the types of patients who will receive the most benefit from the CLASP intervention.                  ","ACTIVITY":"I01","ADMINISTERING_IC":"VA","APPLICATION_TYPE":"1","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"01/24/2014","BUDGET_START":"10/01/2013","BUDGET_END":"09/30/2014","CFDA_CODE":"999","CORE_PROJECT_NUM":"I01HX001275","ED_INST_TYPE":"","FOA_NUMBER":"RFA-HX-12-019","FULL_PROJECT_NUM":"1I01HX001275-01","FUNDING_ICs":"","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"Veterans Affairs","NIH_SPENDING_CATS":"","ORG_CITY":"PROVIDENCE","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"02","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"PROVIDENCE VA  MEDICAL CENTER","ORG_STATE":"RI","ORG_ZIPCODE":"029084734","PHR":" Despite growing concern with increasing rates of suicidal behavior in OEF/OIF veterans, extant interventions have been unable to effectively reduce the suicide rate in veteran populations. The proposed study seeks to test the efficacy of an adjunctive intervention to reduce suicide behaviors in OEF/OIF veterans. The Coping Long Term with Active Suicide Program (CLASP) is an innovative, telephone-based intervention that combines elements of individual psychotherapy, case management and significant other/family therapy and is designed to be easily integrated into a VA system.  ","PI_IDS":"8824754;","PI_NAMEs":"PRIMACK, JENNIFER MARIE;","PROGRAM_OFFICER_NAME":"","PROJECT_START":"10/01/2013","PROJECT_END":"09/30/2017","PROJECT_TERMS":"Accounting;Area;base;Case Management;Cause of Death;Centers for Disease Control and Prevention (U.S.);Cessation of life;Clinical Research;Clinical Trials;combat;Communities;Conduct Clinical Trials;coping;Country;Data;Department of Defense;design;Diagnosis;Effect Modifiers (Epidemiology);efficacy testing;Elements;Evaluation;Family;Family psychotherapy;Feeling suicidal;follow-up;Gender;Goals;Grant;Growth;Health;Health Care Costs;high risk;Hospitalization;Hospitals;Individual;innovation;Intervention;intervention program;Knowledge;Marines;Mental disorders;Methods;Military Personnel;Modeling;National Institute of Mental Health (U.S.);novel;operation;Outcome;Participant;Patients;Phase;Population;primary outcome;problem solving therapy;programs;Psychiatric Hospitals;Psychiatric therapeutic procedure;psychosocial;Psychotherapy;public health medicine (field);Randomized;Recording of previous events;reducing suicide;Research;Role;Safety;Sampling;Series;Severities;Soldier;suicidal behavior;suicidal morbidity;suicidal risk;Suicide;Suicide attempt;Suicide prevention;suicide rate;Symptoms;System;Telephone;Testing;therapy design;therapy development;Time;treatment as usual;United States;Veterans","PROJECT_TITLE":"Veterans Coping Long Term with Suicide","SERIAL_NUMBER":"1275","STUDY_SECTION":"HSR4","STUDY_SECTION_NAME":"HSR-4  Mental and Behavioral Health","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"1","TOTAL_COST":"","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8646901","ABSTRACT_TEXT":"   DESCRIPTION (provided by applicant):     Substance  use  disorders  (SUD)  are  highly  prevalent  and  result  in  substantial  disability,  morbidity,  and  premature mortality. Research supported by the parent grant of this application (R01DA0191606) has helped to define risk factors for SUD.  Known  risk  factors  for  SUD  span  family  history,  poor  parenting,  traumatic  experiences, personality traits, and recent stressful life events, early-onset substance use, social deviance and  availability of substances. Despite impressive recent progress on the identification of risk factors for SUD, no explicit model has been developed and tested that defines the interrelationships among these variables.    Consistent with NIDA's Five Year Strategic Plan's Prevention Priorities 1 \"To identify the characteristics  and patterns of drug abuse\" and 2 \"To understand how genes, environment, and development influence the  various risk and protective factors for drug abuse\", and Cross-Cutting Priority 2 \"To decrease health disparities  related to drug addiction\", in this competing renewal, we seek to build a theory-driven, comprehensive model of  SUD and  examine  its  invariance  across  substances,  race,  and gender. We  will  use  data  from the  34,653  participants  in  Waves  1  and  2  of  the  National  Epidemiologic  Survey  of  Alcohol  and  Related  Conditions  (NESARC). Three complementary families of statistical techniques (GLM, Oaxaca-type decompositions and  structural  equation  models)  will  be  applied  to  guide  development  of  a  conceptual  model  based  on  the  pioneering research of Professor Kendler that focused on risk factors for major depressive disorder, and that  we have modified (e.g., by including availability of drugs) to study the etiology and course of SUD.   This modified Kendler model provides a comprehensive integration of variables from five developmental stages: childhood, early adolescence, late adolescence, adulthood, and the last year. The risk factors for this model were assessed in all NESARC participants and are widely considered to apply to SUD. Importantly,  many  of  the  risk  factors  are  modifiable  and  amenable  to  change  through  prevention  and  treatment  interventions. We propose to use the modified Kendler conceptual model to examine the following aims: 1) To  investigate the relationship between risk factors and prevalence of substance use and SUD~ 2) To determine  the relationship between risk factors and transition from use to SUD,  remission of SUD, and relapse~ 3) To  examine whether gender and racial/ethnic differences across the course of SUD are due to the differential  distribution or differential effect of the risk factors~ and, 4) To develop and test models of substance use, SUD,  transition from SUD, remission from SUD, and relapse.    At the conclusion of this study, we will have developed and tested a model that integrates a broad range of risk factors for the onset and course of SUD. These models will help to inform the development and targeting of evidence-based prevention and treatment interventions for SUD.                ","ACTIVITY":"R01","ADMINISTERING_IC":"DA","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"03/18/2014","BUDGET_START":"04/01/2014","BUDGET_END":"03/31/2015","CFDA_CODE":"279","CORE_PROJECT_NUM":"R01DA019606","ED_INST_TYPE":"","FOA_NUMBER":"PA-08-124","FULL_PROJECT_NUM":"5R01DA019606-07","FUNDING_ICs":"NIDA:354784\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE ON DRUG ABUSE","NIH_SPENDING_CATS":"","ORG_CITY":"NEW YORK","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"13","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"NEW YORK STATE PSYCHIATRIC INSTITUTE","ORG_STATE":"NY","ORG_ZIPCODE":"100321007","PHR":"  Although the risk of substance use disorders (SUD) is influenced by a broad range of variables, the field lacks a  coherent model for organizing these risk factors. We seek to develop and test a theory-driven, comprehensive  developmental model of SUD and examine its invariance across substances, races and gender.                     ","PI_IDS":"6065118;","PI_NAMEs":"BLANCO, CARLOS;","PROGRAM_OFFICER_NAME":"WEINBERG, NAIMAH Z","PROJECT_START":"04/01/2005","PROJECT_END":"03/31/2017","PROJECT_TERMS":"Address;Adolescence;Adult;Alcohol or Other Drugs use;Alcohols;Area;Attention;base;Characteristics;Childhood;Comorbidity;Complex;Data;Data Set;design;Development;disability;Disease remission;Drug abuse;Drug Addiction;early adolescence;early onset substance use;Environment;Epidemiology;Equation;Etiology;Event;evidence base;experience;Family;Funding;Gender;Genes;Goals;health disparity;Hispanics;Impulsivity;Individual;Intervention;Knowledge;Life;Linear Models;Major Depressive Disorder;Modeling;Morbidity - disease rate;novel strategies;parent grant;Parenting behavior;Participant;Pattern;Personality Traits;Pharmaceutical Preparations;Platelet Factor 4;Premature Mortality;Prevalence;Prevention;Preventive;professor;Race;racial difference;racial/ethnic difference;Recording of previous events;Relapse;Research;Research Support;Risk;Risk Factors;Sampling;Scientific Advances and Accomplishments;Sex Characteristics;Shapes;social;Social support;Societies;Staging;Strategic Planning;Substance Use Disorder;Surveys;Techniques;Testing;theories;Work","PROJECT_TITLE":"Towards a Comprehensive Developmental Model of Substance Use Disorders","SERIAL_NUMBER":"19606","STUDY_SECTION":"CIHB","STUDY_SECTION_NAME":"Community Influences on Health Behavior","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"7","TOTAL_COST":"354784","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8858731","ABSTRACT_TEXT":"The Urea Cycle Disorders Consortium's Administrative Unit coordinates all UCDC activities and is led by UCDC principal investigator/director, Mark L, Batshaw, MD. Co-principal investigators have spefic roles to ensure that the Consortium operates smoothly. Dr. Mendel Tuchman serves as Administrative Director and Co-PI, leading the the consortium when Dr, Batshaw is unable to do so, assisting Dr. Batshaw with Consortium administration and directing the clinical and pilot projects, Co-Pl Marshall Summar is responsible for industry and international relationships,assists Dr. Batshaw withUCDC administration and with Dr. Brendan Lee co-directs the training program: Co-Pl Cynthia LeMons is the executive director of the National Urea Cycle Disorders Foundation and serves as an advisor to the UCDC leadership, representing patients'interests in major UCDC decisions. She will also direct external communications from the UCDC to the patient community. Dr. Robert McCarter from Biostatistics and Study Design Unit at Children's Medical Center and Dr. Jeffrey Krischer from the Data Management and Coordinating Center at University of South Florida will advise the UCDC leadership on study design and results analysis. In addition to the directors. Dr. Brendan Lee at Baylor College of Medicine directs the training program, project manager Jennifer Seminara is responsible for UCDC operations, and Arlene Gendron assists with administrative duties. The UCDC holds monthly conference calls and one annual in-person meeting: The DMCCs audit program ensures quality data and is supplemented by a monitoring program directed by the UCDC project manager.","ACTIVITY":"U54","ADMINISTERING_IC":"HD","APPLICATION_TYPE":"2","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"08/22/2014","BUDGET_START":"08/25/2014","BUDGET_END":"07/31/2015","CFDA_CODE":"","CORE_PROJECT_NUM":"U54HD061221","ED_INST_TYPE":"","FOA_NUMBER":"RFA-TR-13-002","FULL_PROJECT_NUM":"2U54HD061221-11","FUNDING_ICs":"NICHD:172208\\","FUNDING_MECHANISM":"Research Centers","FY":"2014","IC_NAME":"EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT","NIH_SPENDING_CATS":"","ORG_CITY":"WASHINGTON","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"98","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"CHILDREN'S RESEARCH INSTITUTE","ORG_STATE":"DC","ORG_ZIPCODE":"200102916","PHR":"Effective administration ensures that the Urea Cycle Disorders Consortium meets its research, education and training goals on budget.","PI_IDS":"1863071;","PI_NAMEs":"BATSHAW, MARK L.;","PROGRAM_OFFICER_NAME":"","PROJECT_START":"08/25/2014","PROJECT_END":"07/31/2019","PROJECT_TERMS":"Award;Biometry;Budgets;Child;Child health care;Clinical;Clinical Research;Clinical Sciences;Collaborations;college;Communication;Communities;Data;data management;Data Quality;Disease;Effectiveness;Ensure;Evaluation;Florida;Foundations;Goals;Guidelines;Health Insurance Portability and Accountability Act;Home environment;Human Development;human subject protection;Industry;Institutes;interest;International;Leadership;Marshal;Medical center;Medicine;meetings;Minority;Monitor;operation;Patients;Persons;Pilot Projects;Policies;Principal Investigator;Procedures;Productivity;programs;Rare Diseases;Regulation;Research;Research Design;Resources;Role;Safety;Site;Structure;symposium;Training and Education;Training Programs;Translational Research;United States National Institutes of Health;Universities;urea cycle;web site;Woman","PROJECT_TITLE":"Overall Adminstration of Rare Diseases Clinical Research Consortia (RDCRC) ","SERIAL_NUMBER":"61221","STUDY_SECTION":"ZTR1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"6838","SUFFIX":"","SUPPORT_YEAR":"11","TOTAL_COST":"","TOTAL_COST_SUB_PROJECT":"172208"}
{"APPLICATION_ID":"8640066","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): The San Diego State University-Minority Health and Health Disparities International Research Training program (SDSU-MHIRT) will continue its eighteen year tradition of providing outstanding international biomedical research training experiences to students from health disparity backgrounds. SDSU-MHIRT encourages and supports its students so that they can successfully pursue careers in the fields of basic and biomedical science, and clinical and behavioral health, and most importantly increase the number of persons from health disparities populations who enter into the field of biomedical science/practice. Twelve trainees per year will perform original research in areas encompassing: public health, molecular biology/ethno-pharmacology, drug design and anticancer agents, behavioral science, marine science, and clinical research. Each foreign site is required to have adequate equipment and human or animal- subject research approval for the execution of the MHIRT trainees'research proposals. Mentorship will be provided at the international sites through both a US and foreign faculty mentor. Sites and mentors have been designated based on their ability to provide a sound research experience. There are several factors unique to this proposal. The first is that SDSU has recently been designated an Hispanic Serving Institution;this, coupled with our proximity to the US-Mexico border and our already thriving cross- border research relationships, affords up the opportunity to provide relevant research experiences to our students. Additionally, our MHIRT trainees will have an extended support system once they return to SDSU. The student-based international research experience is part of an integrated approach in which other training programs (e.g., MBRS, MARC) continue to support the students through their final years here. Major SDSU-MHIRT sites are in Ghana, Mexico, Peru, and Taiwan (Republic of China). A new site - Uganda - is being proposed. Since being awarded for this current cycle, the SDSU-MHIRT program has served 70 trainees. Of these, 9 have been accepted into, are in, or have completed PhD programs and 10 are in Master's programs. In addition, 10 are applying to r medical school, 2 have Fulbright awards, 2 are in the Peace Corps, 5 are working in the field, 2 have been accepted into Pharmacy School, and 30 are still completing their undergraduate education. The new cadre of MHIRT students for 2013 will consist of an additional 12 students taking part in the MHIRT program. In addition, in this cycle 52 publications were produced of which 27 had trainee authors. The program has compiled for the first time a digital database of ethno-botanical plants that is freely accessible n the web. SDSU-MHIRT proposes for this next five year cycle a targeted minimum of 20 trainees accepted into PhD programs, 10 into Master's programs, and 5 into Medical Sciences.         ","ACTIVITY":"T37","ADMINISTERING_IC":"MD","APPLICATION_TYPE":"2","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"11/22/2013","BUDGET_START":"12/01/2013","BUDGET_END":"11/30/2014","CFDA_CODE":"375","CORE_PROJECT_NUM":"T37MD001442","ED_INST_TYPE":"GRADUATE SCHOOLS","FOA_NUMBER":"RFA-MD-13-002","FULL_PROJECT_NUM":"2T37MD001442-17","FUNDING_ICs":"NCMHD:268063\\","FUNDING_MECHANISM":"Other Research Related","FY":"2014","IC_NAME":"NATIONAL CENTER ON MINORITY HEALTH AND HEALTH DISPARITIES","NIH_SPENDING_CATS":"","ORG_CITY":"SAN DIEGO","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"NONE","ORG_DISTRICT":"53","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"SAN DIEGO STATE UNIVERSITY","ORG_STATE":"CA","ORG_ZIPCODE":"921821901","PHR":"PUBLIC HEALTH RELEVANCE: The San Diego State University Minority Health and Health Disparities International Research Training (SDSU-MHIRT) program proposes to continue its eighteen-year tradition of providing an outstanding international biomedical research training experience to students from health disparity backgrounds. The SDSU-MHIRT program encourages and supports its students so that they can successfully pursue careers in the fields of basic science, biomedical, clinical, and behavioral health, and - most importantly - increase the number of persons from health disparities populations who enter into the fields of biomedical science and clinical practice.                 ","PI_IDS":"9170689;","PI_NAMEs":"PLEMMONS, DENA;","PROGRAM_OFFICER_NAME":"BERZON, RICHARD ","PROJECT_START":"09/30/1995","PROJECT_END":"11/30/2018","PROJECT_TERMS":"animal research subject;Antineoplastic Agents;Area;Award;base;behavioral health;Behavioral Sciences;Biomedical Research;Border Crossings;Botanicals;career;CCL7 gene;Clinical Research;Clinical Sciences;Coupled;Databases;digital;Doctor of Philosophy;Drug Design;Equipment;experience;Faculty;Ghana;health disparity;Hispanics;Human;Institution;International;Internet;Marines;Medical;medical schools;Mentors;Mentorship;Mexico;Minority Health and Health Disparities International Research Training;Molecular Biology;Peace Corps;Persons;Peru;Pharmacology;Pharmacy Schools;Plants;Population;programs;public health medicine (field);Publications;Research;Research Proposals;Research Training;Science;Site;sound;Students;Support System;Taiwan;Time;Training Programs;Uganda;undergraduate education;Universities;Work","PROJECT_TITLE":"Minority Health &Health Disparities International Research Training Program","SERIAL_NUMBER":"1442","STUDY_SECTION":"ZMD1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"17","TOTAL_COST":"268063","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8876794","ABSTRACT_TEXT":"We propose to develop a hub by the name Partnership for Mental Health Development in Sub-Saharan  Africa (PaM-D). The hub is aimed at creating an infrastructure to develop mental health (MH) research  capacity in Sub-Saharan Africa (SSA) and to advance global MH science by conducting innovative public  health-relevant MH research in the region. The hub will bring together institutions in six countries in great  need for major improvements in their health systems: Nigeria, South Africa, Ghana, Kenya, Sierra Leone and  Liberia with outstanding researchers from institutions in the US and UK, in partnership with government  departments and non-governmental organizations. It will consist of a multidisciplinary team of internationally  renowned researchers whose direct experience about the complex and peculiar mental health situations in  Africa will be channeled towards addressing the diverse needs associated with low policy priority for mental  health, extreme paucity of human resources, poor community awareness, low recognition of mental health  conditions and under-treatment of those conditions.  The aims include: (1) bringing together service providers, policy makers, and researchers with expertise in  global MH to create a Sub-Saharan MH Research Hub that will establish itself as a regional center  supporting research capacity-building and innovative MH service development in the region, focusing,  initially, on expanding service for persons suffering from one of the most disabling mental health problems:  psychosis and (2) developing and implementing targeted programs of training and mentoring that build  mental health research capacity in a broad range of mental health professionals with a view to creating and  supporting a critical mass of experts for innovative mental health research to address the region's mental  health needs.","ACTIVITY":"U19","ADMINISTERING_IC":"MH","APPLICATION_TYPE":"3","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"09/25/2014","BUDGET_START":"07/01/2014","BUDGET_END":"06/30/2015","CFDA_CODE":"","CORE_PROJECT_NUM":"U19MH098718","ED_INST_TYPE":"","FOA_NUMBER":"RFA-MH-12-110","FULL_PROJECT_NUM":"3U19MH098718-03S2","FUNDING_ICs":"NIMH:32819\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF MENTAL HEALTH","NIH_SPENDING_CATS":"","ORG_CITY":"IBADAN","ORG_COUNTRY":"NIGERIA","ORG_DEPT":"","ORG_DISTRICT":"","ORG_DUNS":"","ORG_FIPS":"NI","ORG_NAME":"UNIVERSITY OF IBADAN","ORG_STATE":"","ORG_ZIPCODE":"200001","PHR":"Most countries in Sub-Saharan Africa are in great need of MH service scale-up to address the growing  burden of MH conditions. The proposed hub will conduct empirical research on task-shifting approaches with  potentials to help the countries meet this need.. Capacity for mental health research will be developed in a  broad range of professionals to create a critical mass of researchers able to secure research funding,  address community's mental health needs and provide evidence for mental health policy development.","PI_IDS":"10520463;","PI_NAMEs":"GUREJE, OYEWUSI;","PROGRAM_OFFICER_NAME":"","PROJECT_START":"07/01/2014","PROJECT_END":"06/30/2017","PROJECT_TERMS":"Achievement;Address;Africa;Africa South of the Sahara;African;Awareness;Caring;Centers of Research Excellence;Communities;Complex;Country;design;Development;Discipline;dissemination research;Economic Development;Empirical Research;Evolution;experience;Funding;Ghana;Goals;Government;Health;health economics;Health Personnel;Health Policy;Health Professional;Health Sciences;Health Services Needs;Health system;Healthcare;Human Resources;Human Rights Abuses;improved;Individual;innovation;Institution;International;Kenya;Knowledge;Liberia;Medicine;meetings;Mental Health;Mental Health Services;Mentally Ill Persons;Mentors;Movement;multidisciplinary;Names;Nigeria;Outcome;Persons;Physicians;Play;Policies;Policy Developments;Policy Maker;programs;Provider;Psychiatry;Psychotic Disorders;public health medicine (field);Reporting;Research;Research Infrastructure;Research Personnel;Research Support;Research Training;Resources;response;scale up;Secure;Series;Services;Sierra Leone;South Africa;Specialist;Training;Training Programs;World Health;Writing","PROJECT_TITLE":"Administration Core - Partnerships for Mental Health Development in Sub-Saharian Africa   ","SERIAL_NUMBER":"98718","STUDY_SECTION":"ZMH1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"6694","SUFFIX":"S2","SUPPORT_YEAR":"3","TOTAL_COST":"","TOTAL_COST_SUB_PROJECT":"32819"}
{"APPLICATION_ID":"8744820","ABSTRACT_TEXT":"Normal tissue toxicity to the gastrointestinal (Gl) tract occurs frequently with chemoradiotherapy and represents a major clinical challenge. Unfortunately, no effective treatments exist to combat this significant clinical problem. The luminal epithelia of the Gl tract exist in physiologic hypoxia, and thus hypoxic signaling is crucial to the their survival and normal functions. Hypoxia-inducible factor-1 (HlF-1) is a transcription factor at the heart of the cellular hypoxia response whose levels fluctuate inversely with cellular oxygen tension. Stabilized HIF-1 expression has been shown to be critical for normal intestinal homeostasis as well as survival during inflammatory challenges. HIF-1 is required to maintain several basic functions of the intestine, such as barrier and absorptive functions. Augmenting HIF-1 expression in the intestine improves epithelial barrier functions, increases nutrient absorption and reduces apoptosis in response to infection and inflammatory stress. Conversely, intestinal specific knockouts of HIF-1 cause increased epithelial apoptosis in murine models of colitis. The oxygen dependent regulation of HIF is chiefly mediated through the prolyl hydroxylase domain (PHD)-containing proteins which hydroxylate proline moieties on HIF, and serve as a recognition site for the von Hippel Lindau (VHL) protein, which targets HIF for proteasomal destruction. To date, three oxygen-dependent prolyl hydroxylases have been identified (PHD1-3), however, the roles of each isoform in intestinal homeostasis is not clear. Because PHD proteins regulate HIF levels, and HIF, in turn protects the gut from inflammatory stress, it is our hypothesis that the PHD proteins regulates radiosensitivity in the gastrointestinal tract, such that deletion of specific PHD isoforms will afford radioprotection of the gut through HIF-medlated effects on epithelial integrity and crypt regeneration. In this proposal, we will: 1) investigate the specific contributions of PHD 1-3 on radioprotecting the Gl tract from hypofractionated and fractionated radiation with Project 2 and Core B, 2) determine the mechanisms of radioprotection by PHD inhibition with Project 3;3) explore the role of PHD 1-3 in the radiation response ofthe intestinal stem cell with Project 2, 4) determine the efficacy of a small molecule PHD inhibitor to protect the Gl tract with Project 2;and 5) determine the therapeutic efficacy of PHD 1-3 knockouts and small molecule inhibitors of PHD activity on tumor growth in response to radiation relative to normal tissue radioprotection with Project 4. This project represents a new paradigm change in the development of radioprotectors in that we are investigating the physiological basis of tissue radioprotection through alterations in epithelial barrier function.","ACTIVITY":"P01","ADMINISTERING_IC":"CA","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"05/29/2014","BUDGET_START":"06/01/2014","BUDGET_END":"05/31/2015","CFDA_CODE":"","CORE_PROJECT_NUM":"P01CA067166","ED_INST_TYPE":"","FOA_NUMBER":"PAR-12-005","FULL_PROJECT_NUM":"5P01CA067166-17","FUNDING_ICs":"NCI:746922\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL CANCER INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"STANFORD","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"18","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"STANFORD UNIVERSITY","ORG_STATE":"CA","ORG_ZIPCODE":"943041222","PHR":"Gastrointestinal (Gl) toxicity is one of the most common and distressing acute side effects of systemic chemotherapy or abdominopelvic radiation therapy. For instance, nearly 75% of patients receiving pelvic radiotherapy experience acute radiation proctopathy, which often involves diarrhea and cramping. The sensitivity of the normal cells in the Gl tract limits dose escalation of radiotherapy to tumors in the abdomen or pelvis, and thereby hinder tumor eradication. Therefore, the need exists for a Gl tract radioprotector.","PI_IDS":"1886037;","PI_NAMEs":"GIACCIA, AMATO J.;","PROGRAM_OFFICER_NAME":"","PROJECT_START":"","PROJECT_END":"","PROJECT_TERMS":"ABCB1 gene;Abdomen;absorption;Acute;Adverse effects;Affect;angiogenesis;Animal Model;Apoptosis;base;Biological Assay;CDX2 gene;Cell Hypoxia;Cells;Cessation of life;chemoradiation;chemotherapy;Clinical;Colitis;Colon;combat;Data;Development;Diarrhea;Distress;DNA Damage;Dose;Dose-Limiting;effective therapy;enema administration;Epithelial;Epithelium;Erythropoiesis;experience;fluorescein isothiocyanate dextran;gastrointestinal;Gastrointestinal tract structure;Genes;Heart;Human;Hypoxia;hypoxia inducible factor 1;Immunohistochemistry;improved;In Situ Nick-End Labeling;in vivo Model;Infection;Inflammatory;inhibitor/antagonist;intestinal epithelium;intestinal homeostasis;Intestines;intraperitoneal;Knock-out;Knockout Mice;Link;Measurement;Measures;Mediating;Metabolic;Modeling;Molecular;Mus;Muscle Cramp;Natural regeneration;Normal Cell;Normal tissue morphology;Nude Mice;Nutrient;Oral;Oxygen;Oxygen measurement, partial pressure, arterial;Pathway interactions;Patients;Pelvis;Pharmacodynamics;Pharmacologic Substance;Physiological;Population;Procollagen-Proline Dioxygenase;Proline;Protein Isoforms;Proteins;Radiation;Radiation therapy;Radiation Tolerance;Radioprotection;Regimen;Regulation;Relative (related person);research study;response;Role;Route;Signal Transduction;Site;small molecule;Staining method;Stains;stem cell population;Stem cells;Stress;subcutaneous;Tertiary Protein Structure;Testing;Therapeutic;Tissues;Toxic effect;transcription factor;Transgenes;Transgenic Animals;Treatment Efficacy;tumor;tumor eradication;tumor growth;VHL protein;villin;Xenograft Model","PROJECT_TITLE":"Targeting the PHD/HIF Pathway to Mitigate Radiation Induced Gl Toxicity","SERIAL_NUMBER":"67166","STUDY_SECTION":"ZCA1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"7498","SUFFIX":"","SUPPORT_YEAR":"17","TOTAL_COST":"","TOTAL_COST_SUB_PROJECT":"746922"}
{"APPLICATION_ID":"8705323","ABSTRACT_TEXT":"   DESCRIPTION (provided by applicant): The scientific issues of this project are focused around four core developmental phenomena of the 18-23 year old period: 1) this period is normatively the highest alcohol consumption interval in the life course;2) toward the end of this interval, for the majority of young adults, a decrease in consumption begins to take place;3) for a higher risk subset of the population, the high consumption pattern continues;and 4) while these critical behavioral shifts are occurring, the neural networks responsible for effortful control and reward response/incentive reactivity are also maturing, albeit at different rates. Three corollary, as yet unanswered questions critical to both social policy about youthful drinking and intervention, are to be addressed: A) To what degree are the changes in drinking behavior taking place over this developmental interval attributable to the maturation of these neural networks?;B) Does heavy alcohol consumption influence the maturation of these networks?;C) How do social environmental reinforcers and prior individual differences in risk mediate or moderate both of these outcomes? During the past 5 years, this project has investigated neurocognitive and functional brain indicators of later problem alcohol use, identifying trajectories of problem use and neural indicators of risk and resilience. This revised continuation project builds on this prior work by extending the investigation into early adulthood and identifying effects of heavy drinking on personality, neurocognition and brain function as well as the interactions between early risk, heavy drinking, and social context (social supports, peer drinking, environmental insults) throughout adolescence and early adulthood. Subjects are participants in the Michigan Longitudinal Study, a high risk for alcohol use disorder family study that has been characterizing temperament, behavioral risk and social context since early childhood and neurocognitive risk since early adolescence. Associated brain function has been studied using fMRI since late adolescence in a subset of these participants. Over the next 5 years, the study will probe the two domains of Effortful Control, and Incentive Reactivity, assessed at the levels of brain function (Regulation/dysregulation of frontostriatal and frontolimbic circuitry and connectivity), neurocognition, and personality. Neurocognitive and personality assessments will continue at 3 year intervals (N= 1456), starting at age 12;a subset of participants (N = 225) will continue to be assessed yearly via fMRI starting at age 18. An important new focus of the imaging work is the interaction between frontal and subcortical processes, to be explored longitudinally using a delayed discounting task, and frontostriatal and frontolimbic functional connectivity analyses. Results will developmentally characterize the relationship between drinking behavior, social environment, and brain function and connectivity change. A special focus is the extent to which drinking behavior lags brain change or leads it, and the role that social environment plays in moderating such change.      ","ACTIVITY":"R01","ADMINISTERING_IC":"AA","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"07/23/2014","BUDGET_START":"08/01/2014","BUDGET_END":"07/31/2015","CFDA_CODE":"273","CORE_PROJECT_NUM":"R01AA012217","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"PA-10-067","FULL_PROJECT_NUM":"5R01AA012217-14","FUNDING_ICs":"NIAAA:609530\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM","NIH_SPENDING_CATS":"","ORG_CITY":"ANN ARBOR","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"PSYCHIATRY","ORG_DISTRICT":"12","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF MICHIGAN","ORG_STATE":"MI","ORG_ZIPCODE":"481091274","PHR":" This project is likely to promote a more in-depth understanding about the intermediate neural pathways underlying susceptibility to heavy drinking and alcohol use disorder at an age interval when both of these phenomena reach their peak. Results will provide new knowledge of how temperament, behavior, brain networks and social environmental risk interact, influencing stability and change in drinking behavior and brain functional networks at arguably the most critical developmental period for alcohol use in the lifespan. Findings will have implications for early identification, prevention, and early treatment of at risk individuals, as well as those in the early stages of an alcohol abusing career.         ","PI_IDS":"6879000;1862210 (contact);","PI_NAMEs":"HEITZEG, MARY M;ZUCKER, ROBERT ALPERT (contact);","PROGRAM_OFFICER_NAME":"BECHTHOLT, ANITA ","PROJECT_START":"06/01/2000","PROJECT_END":"07/31/2016","PROJECT_TERMS":"Address;Adolescence;Adult;Age;Alcohol abuse;Alcohol consumption;alcohol involvement;Alcohol or Other Drugs use;alcohol risk;alcohol use disorder;Alcoholism;Amygdaloid structure;Animals;Attention;Back;base;Behavior;Behavior Control;Behavioral;Biological Neural Networks;Brain;career;Communities;Consumption;critical developmental period;Cues;Development;discounting;Distal;drinking;drinking behavior;Drug usage;early adolescence;early childhood;Early identification;Early treatment;emerging adult;Environmental Risk Factor;Family Study;Functional Magnetic Resonance Imaging;Gambling;Goals;Heavy Drinking;high risk;Human;Image;Impairment;Incentives;Individual;Individual Differences;Intervention;Investigation;Iowa;Knowledge;Life;Life Cycle Stages;Longevity;Longitudinal Studies;Maps;Medial;Mediating;Mediation;Mediator of activation protein;Michigan;Neighborhoods;neural circuit;Neural Pathways;Neurocognition;Neurocognitive;Neurophysiology - biologic function;neuropsychological;operation;Outcome;Participant;Pattern;peer;Personality;Personality Assessment;Play;Population;Predisposition;prevent;Prevention;Process;programs;psychologic;public health medicine (field);Regulation;reinforcer;relating to nervous system;resilience;response;Rewards;Risk;Risk-Taking;Role;Sampling;Services;Short-Term Memory;social;Social Environment;Social Network;Social Policies;Social support;Staging;Substance Use Disorder;System;Temperament;Time;Ventral Striatum;Work;young adult","PROJECT_TITLE":"Neurocognitive Risk For Alcoholism Into Adulthood","SERIAL_NUMBER":"12217","STUDY_SECTION":"APDA","STUDY_SECTION_NAME":"Adult Psychopathology and Disorders of Aging Study Section","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"14","TOTAL_COST":"609530","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8600249","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): Dopamine (DA) is a critical neuromodulator in neural circuits for motor control, cognition and reward. A chief target of DA modulation is signaling of the excitatory neurotransmitter, glutamate. What are the basic principles for DA modulation of glutamatergic signaling and plasticity? Data addressing this question are maddeningly complex. Much of this complexity may be due to variations between cell types and circuits in which DA has been studied. What other factors might contribute to the heterogeneity? Using an ex vivo brain slice preparation of the nucleus accumbens (NAc)-a central component of the neural reward circuit-our pilot studies provide evidence for two additional factors: 1) in vivo exposure t novel stimuli and 2) the timing of DA signaling in relation to long-term potentiation (LTP) induction. We find that a brief exposure to novelty enables DA to induce a long-lasting depression in NAc AMPAR synaptic strength. We also find that prior DA signaling boosts the ability of tetanic stimulation to induce robust LTP. Using direct and sensitive electrophysiologica measures, we will investigate the roles for novelty and timing in DA modulation of NAc AMPARs. We expect our studies to inform new guiding principles for dopamine modulation in health and disease.    ","ACTIVITY":"R21","ADMINISTERING_IC":"DA","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"12/20/2013","BUDGET_START":"01/01/2014","BUDGET_END":"12/31/2014","CFDA_CODE":"279","CORE_PROJECT_NUM":"R21DA033457","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"PA-11-261","FULL_PROJECT_NUM":"5R21DA033457-02","FUNDING_ICs":"NIDA:190000\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE ON DRUG ABUSE","NIH_SPENDING_CATS":"","ORG_CITY":"MINNEAPOLIS","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"NEUROSCIENCES","ORG_DISTRICT":"05","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF MINNESOTA","ORG_STATE":"MN","ORG_ZIPCODE":"554552070","PHR":"PUBLIC HEALTH RELEVANCE: Dopamine is a critical neuromodulator in neural circuits for motor control, cognition and reward, and one of its chief targets is glutamate signaling. Using brain slice electrophysiology in reward circuits, we will investigate the role of two unexplored factors in dopamine modulation of glutamate: novelty experience and timing. We expect our studies to inform new guiding principles for dopamine modulation in health and disease.        ","PI_IDS":"3087233;","PI_NAMEs":"THOMAS, MARK JOHN;","PROGRAM_OFFICER_NAME":"SORENSEN, ROGER ","PROJECT_START":"01/01/2013","PROJECT_END":"12/31/2014","PROJECT_TERMS":"Address;Amygdaloid structure;Animals;Brain;cell type;Characteristics;Chemosensitization;Cognition;Complement;Complex;Corpus striatum structure;Data;Disease;Dopamine;Dopamine Receptor;Drug Addiction;Electrophysiology (science);Excision;experience;Exposure to;Glutamates;Goals;Health;Heterogeneity;Hippocampus (Brain);Home environment;Hour;improved;in vivo;Incentives;interest;Knowledge;Learning;Long-Term Potentiation;Measures;Mediating;Mental Depression;Molecular;Motivation;motor control;Mus;neural circuit;Neuromodulator;Neurons;neurotransmission;Neurotransmitters;novel;Nucleus Accumbens;Parkinson Disease;Pilot Projects;Play;Preparation;Property;Psychological reinforcement;public health relevance;Publishing;Receptor Activation;Recording of previous events;relating to nervous system;Relative (related person);Reporting;research study;Rewards;Role;Schizophrenia;Signal Transduction;Slice;Specificity;Stimulus;Synapses;synaptic depression;Synaptic plasticity;Synaptic Transmission;Testing;Tetanus;Time;Variant","PROJECT_TITLE":"Factors that govern the role of dopamine in striatal AMPAR plasticity","SERIAL_NUMBER":"33457","STUDY_SECTION":"NTRC","STUDY_SECTION_NAME":"Neurotransporters, Receptors, and Calcium Signaling Study Section","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"2","TOTAL_COST":"190000","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8636891","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): Cocaine abuse is a significant public health problem, with approximately 1.4 million Americans meeting the DSMIV criteria for cocaine dependence and acute overdoses causing nearly 500,000 emergency room visits each year. In spite of this, there are remarkably few effective treatments for cocaine addiction and abuse. Part of the difficulty in the medical treatment of cocaine addiction is that even after successful short-term treatment, environmental cues can evoke craving and drug relapse. Behavioral and neurobiological approaches to memory have identified extinction, in which the relation between the cue and the drug is severed, as a way to eliminate conditioned behavior. A challenge for extinction-based therapies, however, is that extinguished behavior often returns with time or after re-exposure to the drug. In our initial period of support, we examined pharmacological approaches that, when paired with behavioral extinction, generated a rapid and persistent loss of drug-seeking that was resistant to reinstatement challenges (relapse-like behavior). Our focus has been on the regulation of gene expression necessary for long-term memory formation, which involves the concerted action of multiple transcription factors and cofactors that interact with chromatin, a protein complex that packages DNA. Chromatin modification is a main mechanism of epigenetic gene regulation, which is emerging as a major molecular pathway involved in synaptic plasticity and memory storage.  Epigenetic gene regulation has been shown to underlie persistent long-term changes at the cellular level as well as the behavioral level. Importantly, in animal models of addiction, chronic drug exposure induces stable chromatin modification resulting in  stable synaptic plasticity changes, which is  thought  to  drive persistnt  changes in behavior. Considering the substantial overlap in the circuitry involved in drug addiction and learning and memory pathways, the focus of this grant proposal is to modulate learning and memory pathways in order to extinguish drug associated memories. In this renewal application, we focus on a specific mechanism of regulating histone acetylation via histone deacetylase 3 (HDAC3). We use genetic, viral, and pharmacological manipulations to investigate the role of HDAC3 in extinction of cocaine-induced conditioned place preferences and intravenous cocaine self-administration. We hypothesize that HDAC3 is a key negative regulator of extinction of drug-seeking behavior and that HDAC3 modulates extinction via regulation of Nr4a (nuclear orphan receptor) gene family.  In Specific Aim 1, we will use a novel pharmacological approach to determine the role of HDAC3 specifically in memory consolidation during extinction. In Specific Aim 2, we will use a genetic and viral approach to determine the role of long-term modulation of HDAC3 in extinction. In Specific Aim 3, we will use a molecular approach to determine the role of the Nr4a gene family (HDAC3 target genes) in extinction. Our approach promises to elucidate behavioral, systems, and epigenetic mechanisms of extinction and elucidate novel molecular targets for pharmacological interventions.          ","ACTIVITY":"R01","ADMINISTERING_IC":"DA","APPLICATION_TYPE":"2","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"03/04/2014","BUDGET_START":"03/15/2014","BUDGET_END":"02/28/2015","CFDA_CODE":"279","CORE_PROJECT_NUM":"R01DA025922","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"PA-11-260","FULL_PROJECT_NUM":"2R01DA025922-06A1","FUNDING_ICs":"NIDA:534209\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE ON DRUG ABUSE","NIH_SPENDING_CATS":"","ORG_CITY":"PORTLAND","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"OTHER BASIC SCIENCES","ORG_DISTRICT":"03","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"OREGON HEALTH &SCIENCE UNIVERSITY","ORG_STATE":"OR","ORG_ZIPCODE":"972393098","PHR":"PUBLIC HEALTH RELEVANCE: Cocaine addiction is a major public health problem in the United States.  There are no FDA approved  medications for cocaine addiction, but epigenetic mechanisms hold great promise because they result in  stable, long-term changes in cell function that ultimately establish stable behavior.  In this proposal, we will examine a very specific epigenetic mechanism (modulation of histone deacetylase 3) that, when paired with behavioral treatments in a rodent model, may help reverse cocaine seeking and reduce relapse.             ","PI_IDS":"3052482 (contact);8772930;","PI_NAMEs":"LATTAL, KENNON MATTHEW (contact);WOOD, MARCELO ANDRES;","PROGRAM_OFFICER_NAME":"SATTERLEE, JOHN S","PROJECT_START":"09/15/2008","PROJECT_END":"02/28/2019","PROJECT_TERMS":"Abstinence;Accident and Emergency department;Acute;addiction;Affect;American;Animal Model;Applications Grants;attenuation;base;Behavior;Behavior Therapy;Behavioral;Behavioral Mechanisms;Brain region;Cell physiology;Cells;Chromatin;chromatin modification;Chronic;Clinical;Clinical Trials;Cocaine;Cocaine Abuse;Cocaine Dependences;cofactor;Cognitive Therapy;craving;Cues;Deacetylase;DNA Packaging;Dopamine;Drug Addiction;Drug Exposure;drug relapse;drug seeking behavior;Early Gene Transcriptions;effective therapy;Epigenetic Process;Exposure to;Extinction (Psychology);FDA approved;Funding;Future;Gene Expression;Gene Expression Regulation;Gene Family;Gene Targeting;Genes;Grant;Histone Acetylation;histone acetyltransferase;histone deacetylase 3;histone modification;Histones;Immediate-Early Genes;inhibitor/antagonist;insight;Intervention;Intravenous;Lead;Learning;learning extinction;Letters;long term memory;Medical;meetings;Memory;Modeling;Molecular;Molecular Target;Mus;mutant;Neurobiology;Neuronal Plasticity;Neurotransmitters;novel;novel therapeutics;Nuclear Orphan Receptor;Overdose;overexpression;Pathway interactions;Patients;Pharmaceutical Preparations;Phase;preference;Procedures;protein complex;public health medicine (field);public health relevance;Rattus;Regulation;Relapse;Research;research study;Resistance;Rodent Model;Role;Self Administration;Signal Transduction;Site;Synaptic plasticity;System;Testing;therapeutic development;Therapeutic Intervention;Time;transcription factor;Transcriptional Regulation;Translating;United States;virus genetics;Visit;Wood material","PROJECT_TITLE":"Behavioral and epigenetic mechanisms in extinction of cocaine-induced memories","SERIAL_NUMBER":"25922","STUDY_SECTION":"MNPS","STUDY_SECTION_NAME":"Molecular Neuropharmacology and Signaling Study Section","SUBPROJECT_ID":"","SUFFIX":"A1","SUPPORT_YEAR":"6","TOTAL_COST":"534209","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8740033","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): HIV-infected individuals on antiretroviral therapy (ART) are at increased risk for cardiovascular disease (CVD), likely due to chronically increased inflammation. Low-dose methotrexate (LDMTX) appears to reduce CVD risk in people with rheumatoid arthritis, who like those with HIV, have increased levels of inflammation. The NHLBI recently provided funding for a clinical trial targeting the excess inflammation in HIV. That \"Parent Study\" is a randomized, double-blind, placebo-controlled trial that will assess whether 24-week treatment with LDMTX: i) is safe, ii) reduces circulating inflammatory biomarkers and levels of immune cell activation and iii) improves brachial artery reactivity. However, neither the biomarkers nor endothelial function tests measured as part of the parent study will report on atherosclerotic inflammation, (the desired pathobiological target of LDMTX therapy in HIV). As such, the direct evaluation of arterial inflammation would substantially enhance the scientific value of the trial.  We propose to conduct a time sensitive ancillary imaging study whose overall goal is to determine if treating virologically suppressed, HIV-infected individuals with LDMTX will reduce inflammation within the arterial wall. Atherosclerotic inflammation can be non-invasively and reproducibly measured with FDG-PET/CT imaging, a well-validated quantitative technique that can sensitively detect changes in atherosclerotic inflammation and which has been employed in several multi-center trials to measure changes in arterial inflammation in response to anti-inflammatory treatments.  Our central hypothesis is that persistent immune activation results in chronic arterial inflammation, which contributes to the CVD risk observed in HIV. This fully integrated ancillary study would, in a subset of patients enrolled in the parent trial: (i) assess the impact of LDMTX on arterial inflammation, (ii) evaluate mechanisms responsible for arterial inflammation in HIV and iii) explore mechanisms responsible for actions of LDMTX on the artery wall. Accordingly, the proposed study would provide unique and highly complementary information that would greatly increase the knowledge and mechanistic insights gained from Parent Study. The ancillary study has two specific aims1) To determine the impact of anti-inflammatory treatment with LDMTX on arterial inflammation, as assessed by FDG-PET/CT imaging, in virally suppressed HIV-infected individuals., and 2) To evaluate the cellular and biochemical basis of the effect of LDMTX therapy on arterial inflammation in HIV.  We expect that LDMTX therapy will improve arterial inflammation and that this mechanistic, proof-of-concept study will demonstrate the importance of inflammation and immune activation in HIV-associated CVD. This would thus form the basis for event-driven trials to evaluate whether anti-inflammatory strategies reduce CVD risk in individuals with treated HIV infection. Accordingly, the study has the potential to shift the paradigm in the approach to treating atherosclerosis in HIV-infected individuals, and potentially in other populations as well.        ","ACTIVITY":"R01","ADMINISTERING_IC":"HL","APPLICATION_TYPE":"1","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"08/13/2014","BUDGET_START":"08/15/2014","BUDGET_END":"05/31/2015","CFDA_CODE":"837","CORE_PROJECT_NUM":"R01HL122177","ED_INST_TYPE":"","FOA_NUMBER":"RFA-HL-14-004","FULL_PROJECT_NUM":"1R01HL122177-01A1","FUNDING_ICs":"NHLBI:451313\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL HEART, LUNG, AND BLOOD INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"BOSTON","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"07","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"MASSACHUSETTS GENERAL HOSPITAL","ORG_STATE":"MA","ORG_ZIPCODE":"021997603","PHR":"PUBLIC HEALTH RELEVANCE: HIV-infected individuals on effective antiretroviral therapy are at increased cardiovascular disease (CVD) risk because of persistent inflammation. This study will test the hypothesis that inflammation drives CVD risk in HIV infection by evaluating the effects of reducing inflammation using low-dose methotrexate on arterial inflammation and immune activation in treated HIV-infected individuals. (End of abstract)                ","PI_IDS":"2245936;","PI_NAMEs":"TAWAKOL, AHMED A;","PROGRAM_OFFICER_NAME":"SHAH, MONICA R","PROJECT_START":"08/15/2014","PROJECT_END":"05/31/2018","PROJECT_TERMS":"abstracting;Accounting;Aftercare;AIDS clinical trial group;Ancillary Study;Anti-inflammatory;Anti-Inflammatory Agents;antiretroviral therapy;Arteries;Atherosclerosis;base;Biochemical;Biological Markers;brachial artery;Cardiovascular Diseases;cardiovascular disorder risk;CD14 gene;Cells;Chronic;Clinical Trials;cohort;Collaborations;cytokine;Disease;Dose;double-blind placebo controlled trial;Enrollment;Evaluation;Event;FCGR3B gene;Funding;Future;Goals;HIV;HIV Infections;Image;Immune;immune activation;Immune Cell Activation;improved;Individual;Inflammation;Inflammation Mediators;Inflammatory;insight;Knowledge;Measurement;Measures;Mediator of activation protein;Methotrexate;monocyte;National Heart, Lung, and Blood Institute;National Institute of Allergy and Infectious Disease;Parents;Pathology;Patients;PET/CT scan;Placebos;Population;Positron-Emission Tomography;public health relevance;Randomized;Relative (related person);Reporting;response;Rheumatoid Arthritis;Risk Factors;T-Lymphocyte;Techniques;Testing;Time;tool;uptake","PROJECT_TITLE":"Effect of Low Dose Methotrexate on Arterial Inflammation in HIV","SERIAL_NUMBER":"122177","STUDY_SECTION":"ZHL1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"A1","SUPPORT_YEAR":"1","TOTAL_COST":"451313","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8715787","ABSTRACT_TEXT":"A. Administrative structure and leadership  The leadership of the Washington University Center for Diabetes Translational Research (WU-CDTR) is strengthened by the synergistic abilities of the Director (D. Haire-Joshu: translation of evidence based diabetes and obesity interventions and policies) and Associate Directors (W. Auslander, community partnerships in diabetes prevention;N. White: pediatric diabetes research). This group has worked collaboratively for the past three decades on Diabetes Research &Training Center-Prevention &Control (DRTC-P&C) Core studies and activities. The Administrative Core will supervise all WU-CDTR activities with oversight by the Executive Committee and input from the Internal and External Advisory Committees (see figure 1 below). The diverse interests and expertise of the Executive Committee make them particularly well suited to monitor and manage the varied interests and activities of the WU-CDTR.","ACTIVITY":"P30","ADMINISTERING_IC":"DK","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"08/21/2014","BUDGET_START":"08/01/2014","BUDGET_END":"07/31/2015","CFDA_CODE":"","CORE_PROJECT_NUM":"P30DK092950","ED_INST_TYPE":"","FOA_NUMBER":"RFA-DK-10-009","FULL_PROJECT_NUM":"5P30DK092950-04","FUNDING_ICs":"NIDDK:486753\\","FUNDING_MECHANISM":"Research Centers","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES","NIH_SPENDING_CATS":"","ORG_CITY":"SAINT LOUIS","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"01","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"WASHINGTON UNIVERSITY","ORG_STATE":"MO","ORG_ZIPCODE":"631304862","PHR":"","PI_IDS":"1968127;","PI_NAMEs":"HAIRE-JOSHU, DEBRA;","PROGRAM_OFFICER_NAME":"","PROJECT_START":"","PROJECT_END":"","PROJECT_TERMS":"Advisory Committees;Arbitration;Childhood;Committee Members;Communities;Conflict (Psychology);Diabetes Mellitus;Diabetes prevention;evidence base;Expenditure;expiration;Future;Goals;interest;Intervention;Leadership;meetings;member;Monitor;Obesity;operation;Policies;Prevention;programs;Research;Research Activity;Research Training;Structure;Translational Research;Translations;Universities;Washington;Work","PROJECT_TITLE":"Administrative Core","SERIAL_NUMBER":"92950","STUDY_SECTION":"ZDK1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"5545","SUFFIX":"","SUPPORT_YEAR":"4","TOTAL_COST":"","TOTAL_COST_SUB_PROJECT":"486753"}
{"APPLICATION_ID":"8708207","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease of unknown cause and increasing prevalence in the United States. An estimated 100,000 Americans will die from IPF this year, and aside from lung transplantation, which only 1% will receive, there is no FDA-approved therapy. Over the last decade, a potential role for gastro-esophageal reflux (GER) and microaspiration in the progression of IPF has been suggested. Both acid and non-acid reflux are likely important, and preliminary data from IPF patients suggest  an increased benefit of laparoscopic fundoplication over medical antacid therapy alone in slowing disease  progression. Laparoscopic fundoplication has been safely performed in patients with IPF and other forms of advanced lung disease awaiting lung transplantation. These data provide a compelling argument for a trial of laparoscopic fundoplication in patients with IPF and associated GER.  In the clinical proposal, we hypothesize that the reduction of abnormal GER with laparoscopic fundoplication will slow the progression of IPF as measured by the forced vital capacity (FVC). To address this hypothesis, we propose the following aims:  Aim 1: To determine the impact of laparoscopic fundoplication on change in FVC over 48 weeks in IPF.  Aim 2: To correlate the reduction in acid and non-acid reflux events with change in FVC over 48 weeks in IPF.  Aim 3: To determine the safety of laparoscopic fundoplication in patients with IPF.  Aim 4: To explore the impact of laparoscopic fundoplication on key secondary endpoints over 48 weeks in IPF.  In the ancillary proposal, we will test the hypothesis that abnormal GER contributes to the profibrotic  phenotype of lung epithelial cells in IPF by using molecular biomarkers in the serum, bronchoalveolar lavage,  and airway epithelial cells to assess the biological relevance of the presence and treatment of abnormal  GER.            CLINICAL STUDY            ","ACTIVITY":"UM1","ADMINISTERING_IC":"HL","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"05/30/2014","BUDGET_START":"06/01/2014","BUDGET_END":"05/31/2015","CFDA_CODE":"837","CORE_PROJECT_NUM":"UM1HL119089","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"RFA-HL-12-022","FULL_PROJECT_NUM":"5UM1HL119089-02","FUNDING_ICs":"NHLBI:1942327\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL HEART, LUNG, AND BLOOD INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"SAN FRANCISCO","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"INTERNAL MEDICINE/MEDICINE","ORG_DISTRICT":"12","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF CALIFORNIA, SAN FRANCISCO","ORG_STATE":"CA","ORG_ZIPCODE":"941430962","PHR":"This proposal will test the hypothesis that the reduction of abnormal GER with laparoscopic fundoplication  slows the progression of IPF, and investigate the impact of abnormal GER on the profibrotic phenotype of  lung epithelial cells. We have assembled a group of researchers that is committed to this proposal's  successful completion. The results of this study will directly inform the design of a future definitive phase III  study and provide important insight into the pathobiology of disease progression in IPF.","PI_IDS":"8544857 (contact);1887455;","PI_NAMEs":"COLLARD, HAROLD R (contact);RAGHU, GANESH;","PROGRAM_OFFICER_NAME":"EU, JERRY PC","PROJECT_START":"08/01/2013","PROJECT_END":"05/31/2016","PROJECT_TERMS":"Acids;Acute;Address;Adverse effects;Alveolar;American;Ancillary Study;Animal Model;Antacids;Applications Grants;base;Biological;Biological Markers;Bronchoalveolar Lavage;Case Series;Cessation of life;Chronic;Clinical;Clinical Research;Clinical Trials Design;cohort;Commit;Data;design;Disease;disease characteristic;Disease Progression;Dyspepsia;Dyspnea;electric impedance;Enrollment;Epithelial;Epithelial Cells;Event;evidence based guidelines;experience;FDA approved;Fundoplication;Future;Gastroesophageal reflux disease;Hamman-Rich syndrome;Heartburn;Hospitalization;Hour;improved;Incidence;insight;Intervention;Lung;Lung diseases;Lung Transplantation;Measures;Medical;Minority;Molecular;Monitor;Operative Surgical Procedures;Patients;Pepsin A;phase 3 study;Phase III Clinical Trials;Phenotype;Physiology;Prevalence;Pulmonary Fibrosis;Quality of life;Randomized;Reflux;repaired;Research Personnel;Risk Factors;Role;Safety;Serum;Signal Transduction;standard care;Stomach;Stress;Symptoms;Testing;United States;Vital capacity","PROJECT_TITLE":"Treatment of IPF with Laparoscopic Anti-reflux Surgery","SERIAL_NUMBER":"119089","STUDY_SECTION":"ZHL1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"2","TOTAL_COST":"1942327","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8652485","ABSTRACT_TEXT":"Sexually transmitted infections (STI) with Chlamydia trachomatis are the most common bacterial STI in both  the United States and worldwide and represent a significant public health concern. At present, there are no  biomarkers to reliably predict potentially devastating Chlamydia-associated reproductive complications, such  as infertility and ectopic pregnancy;therefore, development of a chlamydial vaccine is a high priority. The  traditional definition of \"protective immunity\" following chlamydial infection or vaccination includes reduced  bacterial shedding, shortened duration of infection, and diminished chronic tissue damage. However, the  immunologic correlates of protective immunity are less well-defined and have generally included generation  of IgG antibody and a robust CD4+ Th1 response although the latter has also been implicated in pathology  and may not be adequate as a single read-out for immunologic efficacy. The overall goal of this project is to  define the immunologic and cellular responses that contribute to effective generation of Chlamydia  muridarum-specific immunologic memory. We hypothesize that the CD4+ central and effector memory  phenotype elicited following C. muridarum Infection or immunization is a critical determinant of  protective immunity and/or pathology and, as a corollary, that altered IL-23/Th17 responses may result in  inadequate CD4+ T-cell memory responses. Employing a series of in vivo experiments in an established  mouse model, our hypothesis will be tested by the following Specific Aims: 1) Characterize the cellular and  immunologic responses associated with the development of protective CD4+ memory T-cell responses  following Chlamydia muridarum genital tract infection. 2) Evaluate the contribution of the IL-23/Th17  response in generation of effective CD4+ T-cell central and effector memory responses to C. muridarum  genital tract infection. 3) Determine if immunization with killed organisms elicits a different memory response  than natural infection. Information gained from the proposed studies will advance the Project Leader's  immediate and long-term career objectives to expand her technical and analytical research skills, develop  biomarkers for adverse disease outcomes following Chlamydia STI, and translate findings in the basic  immunology laboratory into clinically relevant prevention and intervention strategies for STI. The Project  Leader will integrate enthusiastic mentorship with numerous institutional resources to reach her goal of  becoming an independent investigator with an established scientific niche in genital tract mucosal  immunology.","ACTIVITY":"P20","ADMINISTERING_IC":"GM","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"04/24/2014","BUDGET_START":"05/01/2014","BUDGET_END":"04/30/2015","CFDA_CODE":"","CORE_PROJECT_NUM":"P20GM103625","ED_INST_TYPE":"","FOA_NUMBER":"PAR-09-079","FULL_PROJECT_NUM":"5P20GM103625-03","FUNDING_ICs":"NIGMS:305024\\","FUNDING_MECHANISM":"Research Centers","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES","NIH_SPENDING_CATS":"","ORG_CITY":"LITTLE ROCK","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"02","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIV OF ARKANSAS FOR MED SCIS","ORG_STATE":"AR","ORG_ZIPCODE":"722023500","PHR":"Sexually transmitted Chlamydia trachomatis infections are a significant public health problem due to their  high frequency and risk of reproductive complications, including infertility and ectopic pregnancy. This  project characterizes the immune response to chlamydial infection and immunization to determine the most  effective regimens to protect from infection and chronic chlamydial disease.","PI_IDS":"1888844;","PI_NAMEs":"SMELTZER, MARK S;","PROGRAM_OFFICER_NAME":"","PROJECT_START":"","PROJECT_END":"","PROJECT_TERMS":"adaptive immunity;Adverse effects;Antibodies;Biological Markers;career;CD4 Positive T Lymphocytes;Cells;Centers of Research Excellence;Cervical;chemokine;Chlamydia;Chlamydia Infections;Chlamydia muridarum;Chlamydia trachomatis;Chronic;clinically relevant;cytokine;Data;Development;Disease;Disease Outcome;Ectopic Pregnancy;Environment;Event;Female;Fostering;Frequencies (time pattern);Future;Generations;genital infection;Genital system;Goals;high risk;Hour;human subject;Immune;Immune response;Immunity;Immunization;Immunoglobulin G;Immunologic Memory;Immunologics;Immunology;improved;in vivo;Individual;Infection;Infection prevention;Infertility;Inflammatory Response;Interleukin-17;interleukin-23;Intervention;Killings;Kinetics;Laboratories;Life;Link;Mediating;Mediator of activation protein;meetings;Memory;memory CD4 T lymphocyte;Mentorship;Metric;microbial;Molecular;mouse model;Mus;Natural Immunity;Organism;Pathogenesis;Pathology;Pelvic Inflammatory Disease;Phenotype;Play;Prevalence;prevent;Prevention strategy;programs;public health medicine (field);Publishing;Reading;Recruitment Activity;Regimen;Regulation;Reproduction;reproductive;Research;Research Personnel;research study;Resources;response;Risk;Role;Route;screening;Series;Sexually Transmitted Diseases;skills;Surrogate Markers;T cell response;T memory cell;Testing;Th1 Cells;Therapeutic;Tissues;Translating;translational study;United States;Vaccination;vaccine development;vaccine-induced immunity;Vaccines","PROJECT_TITLE":"Project 2 - Regulation of the T-cell Memory Response in Chlamydia Genital Tract","SERIAL_NUMBER":"103625","STUDY_SECTION":"ZRR1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"7758","SUFFIX":"","SUPPORT_YEAR":"3","TOTAL_COST":"","TOTAL_COST_SUB_PROJECT":"305024"}
{"APPLICATION_ID":"8646917","ABSTRACT_TEXT":"   DESCRIPTION (provided by applicant): Project Summary/Abstract Neuroimaging plays an increasingly important role in the early diagnosis of Alzheimer's disease (AD). The availability of data from large scale, multi-site studies, such as the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Dominantly Inherited Alzheimer's Network (DIAN), provide unprecedented opportunities of improving our understanding of this complicated disease. On the other hand, these large scale, high dimensional imaging data of ever growing size call for the urgent needs of developing and validating robust and automated mapping tools. To become in independent investigator of brain imaging research in AD, the candidate proposes in this K01 application to receive training in multimodal image analysis, clinical diagnosis of AD, MR imaging techniques, and biostatistics. These training activities will greatly augment the candidate's background in neuroimage analysis and establish a solid foundation for his long term goal of being a leading researcher in computer-aided early diagnosis of AD. In the research plan, the candidate will develop and validate a suite of novel tools for the mapping of neuroanatomy during the development and progression of AD using intrinsic geometry of the anatomical structure. In contrast to conventional approaches that align brains in a canonical Euclidean space such as the Talairach atlas, the candidate models the anatomy intrinsically with the eigenfunctions of the Laplace-Beltrami (LB) operator and their Reeb graphs. This spectral approach is invariant to natural pose variations, robust to geometric deformations due to pathology and disease progression, and leads to novel methods for surface reconstruction, modeling, and mapping. The specific aims are: 1. Validate and continue to develop an intrinsic framework for the mapping of sub-cortical structures based on the LB eigenfunctions. 2. Develop and validate an automated system for cortical surface extraction, major sulci identification, and mapping. 3. Develop and validate novel algorithms for multimodal fusion with cortical mapping. The new algorithms will be validated with cognitive measures using data from ADNI and DIAN, and compared with existing methods in terms of the discrimination power in the early diagnosis of AD. The software tools developed in this project will be distributed publicly.      ","ACTIVITY":"K01","ADMINISTERING_IC":"EB","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"06/05/2014","BUDGET_START":"04/01/2014","BUDGET_END":"03/31/2015","CFDA_CODE":"286","CORE_PROJECT_NUM":"K01EB013633","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"PA-10-056","FULL_PROJECT_NUM":"5K01EB013633-04","FUNDING_ICs":"NIBIB:166644\\","FUNDING_MECHANISM":"Other Research Related","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING","NIH_SPENDING_CATS":"","ORG_CITY":"LOS ANGELES","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"NEUROLOGY","ORG_DISTRICT":"37","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF SOUTHERN CALIFORNIA","ORG_STATE":"CA","ORG_ZIPCODE":"900899235","PHR":" Relevance to Public Health The intrinsic modeling tools developed in this project will significantly improve the robustness in large scale mappings of neuroanatomy such as the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Dominantly Inherited Alzheimer's Network (DIAN). The widespread access to these tools will ultimately lead to an enhanced ability to diagnose AD early in clinical practice.            ","PI_IDS":"10234518;","PI_NAMEs":"SHI, YONGGANG;","PROGRAM_OFFICER_NAME":"ERIM, ZEYNEP ","PROJECT_START":"04/01/2012","PROJECT_END":"03/31/2017","PROJECT_TERMS":"abstracting;Algorithms;Alzheimer's Disease;Anatomy;Atlases;base;Biometry;Brain;Brain imaging;Brain Mapping;cerebral atrophy;Classification;Clinical;clinical Diagnosis;clinical practice;Cognitive;Computer Assisted;Data;Data Set;Dementia;Descriptor;Detection;Development;Diagnosis;Diffusion Magnetic Resonance Imaging;disability;Discrimination (Psychology);Disease;Disease Progression;Early Diagnosis;Emotional;Euclidean Space;Family;Fiber;Foundations;Geometry;Goals;Graph;gray matter;Image;Image Analysis;Imaging Techniques;improved;Inherited;Joints;Label;Lead;Magnetic Resonance Imaging;Manuals;Maps;Masks;Measurement;Measures;Methods;Metric;mild cognitive impairment;Modeling;Multimodal Imaging;Neuroanatomy;neuroimaging;Neurologic;novel;Output;Pathology;Patients;Pattern;Perfusion;Play;Population;Prevention;Psychometrics;public health medicine (field);reconstruction;Research;Research Personnel;Role;Sensitivity and Specificity;Series;Site;Societies;Software Tools;Solid;Solutions;Spin Labels;Staging;Structure;Surface;System;Testing;Thick;Tissues;tool;Training;Training Activity;Validation;Variant;white matter","PROJECT_TITLE":"Intrinsic Modeling and Tracking of Neuroanatomy in Alzheimer's Disease","SERIAL_NUMBER":"13633","STUDY_SECTION":"ZEB1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"4","TOTAL_COST":"166644","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8786925","ABSTRACT_TEXT":"DESCRIPTION (provided by applicant):  Brain metastases pose a significant problem for women with advanced metastatic diseases. The rate of brain metastasis has increased significantly in the last 10 years, approaching or exceeding 35% in subpopulations of metastatic breast cancer patients, particularly those with Her2+ or \"triple-negative\" tumors. After diagnosis of multiple metastatic lesions, patients typically die within one to two years. Gap: Treatment of brain metastases is primarily palliative due to limited curative effectiveness of radiation, surger, and poor delivery of chemotherapy across the blood-brain barrier (BBB). This proposal focuses on preventing metastasis seeding and initial growth in brain using preclinical models. Hypothesis: By reducing the efficiency of metastatic cancer cell penetration into brain and increasing drug delivery and efficacy in early micrometastatic lesions, we will decrease large metastases development and improve both neurological function and overall survival. Aim 1: Demonstrate that brain invasion of metastatic breast cancer cells can be inhibited at the level of the BBB: Preliminary data indicate TGF-[unreadable] inhibition reduces brain invasion, at the level of the BBB, of triple negative human metastatic breast cancer cells in vivo ~70-80%. This work is extended to characterize mechanisms of how TGF-[unreadable] inhibition reduces BBB cell invasion and the role Her2+ plays in BBB invasion. Aim 2: Elucidate the causal relationship between blood-tumor barrier permeability changes and chemotherapeutic uptake and effect in brain micrometastases of breast cancer: Preliminary data suggest that, contrary to common assumptions, most micrometastatic lesions (<500 [unreadable]m diameter) of breast cancer in brain show marked changes in metastatic vasculature structure and function, including vessel co- option, reduced vascular density, enhanced permeability, and elevated VEGF expression. In this Aim, work will be completed to characterize BBB changes in micrometastases, with the goal of identifying selective difference in micrometastases, such as VEGF and Notch, which can be used for targeted therapeutic benefit. Aim 3: Develop novel strategies to modulate blood-brain barrier permeability to improve therapeutic efficacy for brain micrometastases treatment: Preliminary data demonstrate that inhibition of vascular endothelial Notch signaling in both large and small brain metastases in the presence of VEGF results in targeted increases in BBB permeability. In this Aim, the targeted increases in permeability are exploited to improve chemotherapy delivery, cytotoxic effect and overall survival in three preclinical tumor models. Impact: The goal of this proposal is to develop novel approaches to reduce breast cancer cell invasion to brain, to modulate BBB permeability and improve chemotherapy uptake into CNS metastases, with an overall purpose to reduce brain metastases related death. The work requires state-of-the-art cell targeting, BBB permeability, and drug distribution methods to link barrier changes in selected small tumors with overall brain metastasis invasion and growth.","ACTIVITY":"R01","ADMINISTERING_IC":"CA","APPLICATION_TYPE":"7","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"05/19/2014","BUDGET_START":"05/19/2014","BUDGET_END":"03/31/2015","CFDA_CODE":"395","CORE_PROJECT_NUM":"R01CA166067","ED_INST_TYPE":"SCHOOLS OF PHARMACY","FOA_NUMBER":"PA-12-270","FULL_PROJECT_NUM":"7R01CA166067-02","FUNDING_ICs":"NCI:297887\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL CANCER INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"MORGANTOWN","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"PHARMACOLOGY","ORG_DISTRICT":"01","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"WEST VIRGINIA UNIVERSITY","ORG_STATE":"WV","ORG_ZIPCODE":"26505","PHR":"PUBLIC HEALTH RELEVANCE:  The proposed research is relevant to public health because brain metastases are becoming increasingly common in women with advanced metastatic breast cancer. Unfortunately, once brain metastases are established and clinically detectable with an MRI, few treatment options are available and patients die within one to two years. Consequently, we are studying ways to prevent metastasis occurrence in brain, and ways to kill metastatic lesions in brain while they are very small, before they become untreatable.","PI_IDS":"7548659;","PI_NAMEs":"LOCKMAN, PAUL R;","PROGRAM_OFFICER_NAME":"FORRY, SUZANNE L.","PROJECT_START":"12/18/2013","PROJECT_END":"03/31/2018","PROJECT_TERMS":"Autopsy;Blood;Blood - brain barrier anatomy;Blood Vessels;Brain;brain tissue;Breast Cancer Cell;Caliber;cancer cell;Cancer Patient;Cells;Cessation of life;chemotherapy;cytotoxic;cytotoxicity;Data;density;Development;Diagnosis;Disease;Disseminated Malignant Neoplasm;Dose;Drug Delivery Systems;drug distribution;drug efficacy;Effectiveness;ERBB2 gene;experience;Extravasation;gamma secretase;Goals;Growth;Growth Factor Inhibition;Growth Factor Receptors;Health;Human;Imaging Techniques;improved;in vivo;inhibitor/antagonist;innovation;Invaded;Killings;Lesion;Life;Link;Magnetic Resonance Imaging;malignant breast neoplasm;Mammary Neoplasms;MDA MB 231;meetings;Metastatic Lesion;Metastatic malignant neoplasm to brain;Metastatic Neoplasm to the Central Nervous System;Methodology;Methods;Micrometastasis;Modeling;Multimodal Imaging;Neoplasm Metastasis;Nervous System Physiology;Neuraxis;notch protein;novel strategies;Outcome;palliative;Patients;Penetration;Permeability;Pharmaceutical Preparations;Phosphotransferases;Play;pre-clinical;Pre-Clinical Model;prevent;Prevention;public health medicine (field);Radiation;Refractory;Relapse;Research;research and development;Resistance;response;Role;Signal Pathway;Signal Transduction;Site;Stable Disease;Structure;Testing;Therapeutic;therapeutic target;therapy development;Transforming Growth Factors;Translating;Treatment Efficacy;tumor;uptake;Vascular Endothelial Growth Factors;Woman;Work","PROJECT_TITLE":"Prevention and treatment of brain micrometastases of breast cancer","SERIAL_NUMBER":"166067","STUDY_SECTION":"DT","STUDY_SECTION_NAME":"Developmental Therapeutics Study Section","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"2","TOTAL_COST":"297887","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8644916","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): More than a decade of research has established that sleep plays a critical role in memory consolidation, contributing to its stabilization, enhancement and integration into existing cortical networks. Despite the critical role of sleep in memory and cognition, abnormal sleep has generally been overlooked as a potential contributor to cognitive deficits in schizophrenia (SZ). This oversight is important as effective treatments for cognitive deficits are lacking and abnormal sleep is a potential treatment target. A burgeoning literature suggests that sleep spindles mediate sleep-dependent memory consolidation and cognitive function more generally. At the same time, several recent studies show that sleep spindles are dramatically reduced in SZ. Our preliminary data are the first to link the sleep spindle deficit wih the impairment of sleep-dependent memory consolidation in SZ that we have now documented in four independent studies. They also provide the first demonstration of reduced coherence of spindles across the cortex. Reduced spindle activity also predicted increased severity of positive symptoms and neurocognitive deficits. The observed spindle abnormalities implicate dysfunction in the spindle-generating thalamocortical feedback loop, which is regulated by both [unreadable]-aminobutyric acid (GABA)ergic and N-methyl-D-aspartate acid (NMDA) receptor mediated glutamatergic neurotransmission, all of which have been implicated in the pathophysiology of SZ. The primary goal of the proposed study is to replicate and extend the findings of our placebo-controlled, double-blind pilot study that eszopiclone (Lunesta), restores sleep spindles and sleep-dependent consolidation of motor procedural memory in SZ to normal levels. Eszopiclone is a non-benzodiazepine hypnotic agent that acts on GABAA receptors in the thalamic reticular nucleus where sleep spindles are generated. We will also determine whether there is more general impairment of sleep-dependent memory in SZ by examining the consolidation of other types of memory that are known to be impaired. Finally, we will establish the clinical relevance of abnormal sleep in SZ by correlating spindle activity and other sleep parameters with cognitive deficits based on standard neuropsychological assessment, symptom presentation, and functional capacity. In summary, our preliminary data suggest that abnormal spindles impair sleep-dependent memory consolidation in schizophrenia, contribute to positive symptoms, and are a promising novel target for the treatment of cognitive deficits in schizophrenia. This project is novel and both clinically and scientifically significant in that if ur hypotheses are confirmed, it will link a specific cognitive deficit to a particular mechanism and provide an effective intervention. Thus, the proposed research program has the potential to substantially expand current models of cognitive deficits in SZ and to lead to interventions that significantly improve the quality of life of individuals with SZ.        ","ACTIVITY":"R01","ADMINISTERING_IC":"MH","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"03/11/2014","BUDGET_START":"04/01/2014","BUDGET_END":"03/31/2015","CFDA_CODE":"242","CORE_PROJECT_NUM":"R01MH092638","ED_INST_TYPE":"","FOA_NUMBER":"PA-10-067","FULL_PROJECT_NUM":"5R01MH092638-03","FUNDING_ICs":"NIMH:435000\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF MENTAL HEALTH","NIH_SPENDING_CATS":"","ORG_CITY":"BOSTON","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"07","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"MASSACHUSETTS GENERAL HOSPITAL","ORG_STATE":"MA","ORG_ZIPCODE":"021997603","PHR":" Although sleep plays a critical role in learning and memory, abnormal sleep has generally been overlooked as a potential contributor to cognitive deficits in schizophrenia (SZ). This oversight is important as effective treatments for cognitive deficits are lacking and abnormal sleep is a potential treatment target. We will determine whether eszopiclone, a common sleep medication, can normalize sleep and restore sleep- dependent memory processing in patients with SZ, which can result in improved cognitive function and quality of life.                ","PI_IDS":"6099784 (contact);2080386;","PI_NAMEs":"MANOACH, DARA S (contact);STICKGOLD, ROBERT;","PROGRAM_OFFICER_NAME":"MORRIS, SARAH E","PROJECT_START":"07/01/2012","PROJECT_END":"03/31/2015","PROJECT_TERMS":"Acids;Activities of Daily Living;Aminobutyric Acids;Attention;base;Biological Markers;Cell Nucleus;clinically relevant;Cognition;Cognitive deficits;cognitive function;Cross-Over Studies;Data;density;disability;Double-Blind Method;effective intervention;effective therapy;Electroencephalography;Eszopiclone;Failure (biologic function);Feedback;Fingers;Functional disorder;functional outcomes;GABA-A Receptor;gamma-Aminobutyric Acid;Glutamates;Goals;hypnotic;Impaired cognition;Impairment;improved;indexing;Individual;Intervention;Lead;Learning;Link;Literature;Mediating;Memory;Memory impairment;memory process;Modeling;Motor;Motor Skills;N-Methylaspartate;Neurocognitive Deficit;neuropsychological;Neuropsychological Tests;neurotransmission;novel;Outcome;Participant;Patients;Performance;Pharmaceutical Preparations;Pilot Projects;Placebo Control;Placebos;Play;procedural memory;programs;Publishing;Quality of life;receptor;Research;Research Design;restoration;Role;Schizophrenia;Severities;Sleep;Sleep disturbances;Speed (motion);Stage II Sleep;Symptoms;Testing;Thalamic structure;therapy development;Time;Training","PROJECT_TITLE":"Sleep-dependent Memory Processing in Schizophrenia","SERIAL_NUMBER":"92638","STUDY_SECTION":"NPAS","STUDY_SECTION_NAME":"Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"3","TOTAL_COST":"435000","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8605875","ABSTRACT_TEXT":"   DESCRIPTION (provided by applicant): Regulation of fat storage, release and secretion is key to metabolic health. Redox is an important mediator of cell function within cells that is communicated among cells by blood metabolites. Extracellular redox is sensed by fat cells, via metabolites and amino acids, where they may function as master regulators of adipocyte fuel handling and adipokine secretion. The circulating redox metabolites are produced by cells and link all tissues of the body: couples include the thiol (SH/SS) ratios, reflected in the cysteine/cystine and GSH/GSSG ratios, the mitochondrial redox state reflected in the ss-hydroxybutyrate (ss-OHB)/ acetoacetate (Acoc) ratio (B/A) and the cytosolic redox state reflected in the lactate/pyruvate ratio (L/P). Redox ratios change in response to metabolic status (high fat diet, fasting, diabetes), aging, and oxidative stress. Many observations support a causal relationship between redox changes and reactive oxygen and nitrogen species (ROS). During the prior grant period, we demonstrated that adipocytes generate ROS via a mitochondrial mechanism and that scavenging ROS with pyruvate stimulated O2 consumption. We also found that consumption of the ROS scavenger, n-acetyl cysteine, increased respiration and decreased body fat in vivo. Our long-term goal is to improve metabolic health by regulating adipose tissue function. In this application we will identify conditions where redox-mediated ROS generation alters lipid metabolism, adipokine secretion and mitochondrial responses to variations in the extracellular B/A or L/P ratio or thiol oxidation state and applying these findings to animals. We propose that the mechanism for ROS induced regulation of lipolysis involves mitochondrial autophagy and regulation of ROS levels. The application will explore the hypothesis that redox, as a master regulator of metabolic and mitochondrial responses, regulates generation of ROS, the fate of fuels, and adipokine secretion via mitochondrial bioenergetics and autophagy. Aim 1 is to determine the most effective way to impact lipolysis, triglyceride synthesis and adipokine secretion and determine how such changes relate to intracellular redox and ROS generation. These studies will define the metabolites or couples that modulate adipocyte function and the interrelationship if any among them. Aim 2 is to determine the mechanism of RS-induced functional changes on lipid handling and secretion by assessing the effect of the couples on mitochondrial bioenergetics, autophagy and dynamics. These studies will provide mechanistic information and identify proteins whose modification impacts cell function. Aim 3 is to translate redox and RS-induced lipid handling and adipokine secretion by feeding or infusion into animals. These studies will provide the essential underpinning for future human studies to test the validated concepts. The outcome of these studies will determine the feasibility of applying natural redox mechanisms to regulate adipocyte lipid handling and adipokine secretion to improve metabolic health caused by excess fat tissue.      ","ACTIVITY":"R01","ADMINISTERING_IC":"DK","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"03/13/2014","BUDGET_START":"02/01/2014","BUDGET_END":"01/31/2015","CFDA_CODE":"847","CORE_PROJECT_NUM":"R01DK056690","ED_INST_TYPE":"","FOA_NUMBER":"PA-10-067","FULL_PROJECT_NUM":"5R01DK056690-14","FUNDING_ICs":"NIDDK:559478\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES","NIH_SPENDING_CATS":"","ORG_CITY":"BOSTON","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"08","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"BOSTON MEDICAL CENTER","ORG_STATE":"MA","ORG_ZIPCODE":"02118","PHR":"PUBLIC HEALTH RELEVANCE: The rapid increase in the prevalence of obesity is largely attributed to increased caloric intake and decreased expenditure. This study will describe and characterize a novel mechanism by which nutrition leads to obesity. Results from this study will generate new targets for the treatment of obesity and diabetes and may identify components and dietary aspect that lead to fat accumulation rather than utilization.         ","PI_IDS":"1863612 (contact);1884880;7035646;","PI_NAMEs":"CORKEY, BARBARA E. (contact);GUO, WEN;SHIRIHAI, ORIAN S;","PROGRAM_OFFICER_NAME":"HAFT, CAROL R.","PROJECT_START":"12/01/1999","PROJECT_END":"01/31/2016","PROJECT_TERMS":"Acetoacetates;Acute;Adipocytes;Adipose tissue;Affect;Aging;Amino Acids;Animals;Autophagocytosis;Bioenergetics;Blood;Blood Cells;Body fat;Cardiovascular Diseases;Cell membrane;Cell physiology;Cells;Consumption;Couples;Cysteine;Cystine;Data;Diabetes Mellitus;Diet;Dietary Component;Dietary Supplementation;Disease;Energy Intake;Equilibrium;Expenditure;extracellular;Fasting;Fatty acid glycerol esters;Fatty Acids;feeding;Future;Generations;Glutathione;Glutathione Disulfide;Goals;Grant;Health;Homeostasis;Human;Hydroxybutyrates;improved;in vivo;Infusion procedures;ketogentic;Ketones;Kinetics;Lead;Link;lipid metabolism;Lipids;Lipolysis;Mediating;Mediator of activation protein;Membrane Transport Proteins;Metabolic;Mitochondria;mitochondrial autophagy;Modification;molecular imaging;Nitrogen;novel;nutrition;Obesity;obesity treatment;Oils;Organ;Outcome Study;oxidation;Oxidation-Reduction;Oxidative Stress;Oxygen;Pathway interactions;Physiological;Plasma;Play;Prevalence;Proteins;public health relevance;Pyruvate;Reaction;Regulation;Respiration;response;Role;Signal Transduction;Stream;Sulfhydryl Compounds;Testing;Tissues;tool;Translating;Triglycerides;Variant","PROJECT_TITLE":"Metabolic Signal Transduction in Adipocytes","SERIAL_NUMBER":"56690","STUDY_SECTION":"CADO","STUDY_SECTION_NAME":"Cellular Aspects of Diabetes and Obesity Study Section","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"14","TOTAL_COST":"559478","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8789432","ABSTRACT_TEXT":"The various forms of the HIV-1 envelope (Env) glycoproteins do not serve as ideal immunogens because  they poorly induce Abs (Abs) with broad anti-viral functions, and the Ab response lasts <6 months. To  overcome these limitations, epitope-scaffold immunogens can be used to focus the Ab response on  vulnerable sites on the Env;however, the design of HIV epitope-scaffold immunogens has been fraught with  many failures. Nevertheless, epitope-scaffold vaccines candidates have been successfully developed  against influenza and Neisseria, and we and others have succeeded in designing several V3-scaffold and V3  peptide immunogens with demonstrable antigenicity and immunogenicity, resulting in the induction of HIV-1  cross-clade neutralizing Abs. In this Project, we propose to focus the immune response on the V2  region of gpl 20. Until recently, this region was virtually overlooked as a target for vaccine development,  but its importance as a vaccine target has been recently supported by data showing that anti-V2 Abs can be  highly cross-reactive, display neutralizing activity, capture virus particles, and block gp120/a4p7 interaction.  Support for pursuing V2 as a promising antigen for vaccine design also comes from pilot studies with  specimens from the RV144 clinical vaccine trial. For this Project, we will apply the platform we developed for  generating V3-scaffold immunogens to the production of V2-scaffold immunogens to be used for boosting  the Ab response after priming with DNA Env. For Aim 1.1, we will construct V2 inserts for scaffolded  immunogens based on the fine specificity of human V2 polyclonal and monoclonal Abs (mAbs), and on  bioinformatics and molecular modeling data. In Aim 1.2, we will assess the prevalence and function of anti-  V2 Abs of different specificities and clarify how these differ relative to the infecting HIV clade. For Aim 1.3,  we will select and characterize new human V2-specific mAbs derived from non-clade B-infected donors from  Cameroon infected with the clades that induce the most broad and functional anti-V2 Abs. Finally, after  selecting V2-scaffold proteins which, from the results of Aim 1.2 and 1.3, react with the most broad, potent  and multifunctional anti-V2 polyclonal and mAbs, we will, in Aim 1.4, test the immunogenicity of selected V2  scaffold boosting immunogens in rabbits and non-human primates after priming with Env DNA. The  ultimate goal of this Project is to induce antl-V2 Abs in rabbits and non-human primates that display  cross-clade anti-viral activities that mediate protection.","ACTIVITY":"P01","ADMINISTERING_IC":"AI","APPLICATION_TYPE":"3","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"09/04/2014","BUDGET_START":"01/23/2014","BUDGET_END":"01/22/2016","CFDA_CODE":"","CORE_PROJECT_NUM":"P01AI100151","ED_INST_TYPE":"","FOA_NUMBER":"RFA-OD-13-199","FULL_PROJECT_NUM":"3P01AI100151-02S1","FUNDING_ICs":"NIAID:556733\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES","NIH_SPENDING_CATS":"","ORG_CITY":"NEW YORK","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"12","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"NEW YORK UNIVERSITY SCHOOL OF MEDICINE","ORG_STATE":"NY","ORG_ZIPCODE":"100165802","PHR":"RELEVANCE (See instructions):  Novel concepts are needed to develop an effective HIV vaccine. This project's goal is to design new HIV  epitope-scaffold vaccines that will focus the host immune response on vulnerable sites on the V2 loop of the  virus envelope glycoprotein. The project will provide important data that will advance the development of a  more effective HIV vaccine.","PI_IDS":"1874667;","PI_NAMEs":"ZOLLA-PAZNER, SUSAN B;","PROGRAM_OFFICER_NAME":"","PROJECT_START":"01/23/2014","PROJECT_END":"01/22/2016","PROJECT_TERMS":"Accounting;Advanced Development;Antibodies;Antibody -dependent cell cytotoxicity;Antibody Formation;Antigens;base;Bioinformatics;Cameroon;CD8B1 gene;Cells;Chimeric Proteins;Cleaved cell;Clinical Trials;Data;design;DNA;Epitopes;Evolution;Failure (biologic function);flexibility;Glycoproteins;Goals;gp160;Gut associated lymphoid tissue;HIV;HIV Envelope Protein gp120;HIV vaccine;HIV-1;Human;Immune response;immunogenic;immunogenicity;in vivo;Individual;Influenza;innovation;Instruction;Literature;Mediating;Meningitis;Methods;molecular modeling;Molecular Models;Neisseria;nonhuman primate;novel;Oryctolagus cuniculus;pandemic disease;pathogen;Pattern;Peptides;Pilot Projects;Plasma;Prevalence;Prevention;Probability;Production;Protein Engineering;Reagent;Recombinants;Regimen;Relative (related person);Reporting;Research;scaffold;Scaffolding Protein;Serum;Site;Specificity;Specimen;Structure;success;Surface;T cell response;T-Lymphocyte;Testing;Ursidae Family;vaccine candidate;Vaccine Clinical Trial;Vaccine Design;vaccine development;Vaccines;Variant;Viral Physiology;Virion;Virus;virus envelope","PROJECT_TITLE":"Vaccines to Induce Functional Antibodies Targeting the V2 Loop ","SERIAL_NUMBER":"100151","STUDY_SECTION":"ZAI1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"7191","SUFFIX":"S1","SUPPORT_YEAR":"2","TOTAL_COST":"","TOTAL_COST_SUB_PROJECT":"556733"}
{"APPLICATION_ID":"8733196","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): The proposed research offers a unique opportunity to provide exposure-response estimates between measured occupational biomechanical stressors, non-occupational physical activities, demographics, medical history, psychosocial factors;and risk of carpal tunnel syndrome (CTS), lateral epicondylitis (LEPI), and medial epicondylitis (MEPI). Three prospective cohort studies will pool data from 35 US workplaces, representing a wide range of occupations, industries, and physical exposure levels. 1,973 employees were enrolled and 1,698 were followed for up to 110 months (average follow-up = 34 months). Comprehensive data are available on each worker's biomechanical stressors, physical examination maneuvers, and median and ulnar nerve conduction studies at the wrist. Exposure-response relationships will be estimated between biomechanical stressors and the prevalence and incidence of: CTS, LEPI, and MEPI, while adjusting for relevant effect modifiers and confounders. Measures of biomechanical stressors used in this study include established models of ACGIH Threshold Limit Value (TLV) for Hand Activity Level (HAL), and the 1995 Strain Index (SI), as well as newly developed models: (i) Revised Strain Index (RevSI), (ii) Composite Strain Index (COSI), and (iii) Cumulative Strain Index (CUSI). Comprehensive physical exposure data from these studies feature: (i) individual worker exposure with changes in exposure over time, and (ii) detailed data for each combination of force, repetition, and posture (sub-task data). These data allow us to model biomechanical stressors in detail not previously possible using innovative approaches such as RevSI, COSI, and CUSI. The three sites all have comprehensive data on potential confounders and covariates including worker demographics, past medical history, non-occupational hobbies and activities, and psychosocial factors. All sites used matching case definitions for CTS, LEPI, and MEPI that included symptoms plus physical maneuvers and nerve conduction studies. Pooling existing data across the three studies will enable us to estimate the magnitude and shape of the relative risk function across a wider range of biomechanical stressors: (i) with improved confidence and precision, (ii) for workers with job rotation, and (iii) for tasks with multiple combinations of force, repetition, and posture. Results from this proposed research will help employers to design safe and productive jobs and provide public-health agencies and occupational health researchers with information to more effectively guide prevention programs.         ","ACTIVITY":"R01","ADMINISTERING_IC":"OH","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"06/05/2014","BUDGET_START":"09/01/2014","BUDGET_END":"08/31/2015","CFDA_CODE":"","CORE_PROJECT_NUM":"R01OH010474","ED_INST_TYPE":"BIOMED ENGR/COL ENGR/ENGR STA","FOA_NUMBER":"PAR-10-188","FULL_PROJECT_NUM":"5R01OH010474-02","FUNDING_ICs":"NIOSH:271063\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE FOR OCCUPATIONAL SAFETY AND HEALTH","NIH_SPENDING_CATS":"","ORG_CITY":"MILWAUKEE","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"ENGINEERING (ALL TYPES)","ORG_DISTRICT":"04","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF WISCONSIN MILWAUKEE","ORG_STATE":"WI","ORG_ZIPCODE":"532010340","PHR":"PUBLIC HEALTH RELEVANCE: The proposed research offers a unique opportunity to comprehensively study the relationship between job physical demands and upper limb injuries such as carpal tunnel syndrome, tennis elbow (lateral epicondylitis) and golfer's elbow (medial epicondylitis). The study will use innovative methods, never before used, to quantify job physical demands for workers whose tasks have changing levels of force and hand/wrist posture as well as for those workers who have job rotation. Results from this proposed research will help employers to design safe and productive jobs and provide public-health agencies and occupational health researchers with information to more effectively guide prevention programs.              ","PI_IDS":"6369133;","PI_NAMEs":"GARG, ARUN;","PROGRAM_OFFICER_NAME":"KARR, JOAN ","PROJECT_START":"09/01/2013","PROJECT_END":"08/31/2016","PROJECT_TERMS":"","PROJECT_TITLE":"Exposure Response Relationships for CTS and Epicondylitis from Pooled Data","SERIAL_NUMBER":"10474","STUDY_SECTION":"SOH","STUDY_SECTION_NAME":"Safety and Occupational Health Study Section","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"2","TOTAL_COST":"271063","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8652325","ABSTRACT_TEXT":"11.1. Overview: The Operations Core (OC) will function as the unit responsible for centralizing, directing, and  monitoring all scientific and administrative functions of the CCCR, including the Principal Research Core and  the Research Methods Core (Figure 1). In addition, the OC will have the critical responsibility of organizing the ongoing  and consistent interface between CCCR investigators, scientific consultants, and key representatives  from the Collaborative and Family Advocates Research Boards. Specific responsibilities of the OC include:  administrative, organizational, and scientific management and oversight;data management and statistical  consulting;human subjects protections and incorporation of issues specific to culture, race, ethnicity and urban  context into all studies supported by the CCCR. In addition, the OC will organize training for experienced and  new investigators, mentoring and sponsor career development opportunities. Section 11.2 overviews the aims,  while 11.3 highlights the guiding collaborative research frameworks. Sections 11.4 through 11.8 describe  staff/collaborators and,Section 11.9 summarizes specific OC responsibilities. Table 1 (provided in the response  to the reviewer comments) overviews the connection between critical challenge areas within the field of child  mental health services research and the aims of the OC and proposed functions.","ACTIVITY":"P20","ADMINISTERING_IC":"MH","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"03/31/2014","BUDGET_START":"04/01/2014","BUDGET_END":"03/31/2015","CFDA_CODE":"","CORE_PROJECT_NUM":"P20MH085983","ED_INST_TYPE":"","FOA_NUMBER":"PAR-08-087","FULL_PROJECT_NUM":"5P20MH085983-05","FUNDING_ICs":"NIMH:387764\\","FUNDING_MECHANISM":"Research Centers","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF MENTAL HEALTH","NIH_SPENDING_CATS":"","ORG_CITY":"NEW YORK","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"13","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI","ORG_STATE":"NY","ORG_ZIPCODE":"100296574","PHR":"","PI_IDS":"1872610;","PI_NAMEs":"MCKAY, MARY MCKERNAN;","PROGRAM_OFFICER_NAME":"","PROJECT_START":"","PROJECT_END":"","PROJECT_TERMS":"Advocate;Area;career development;Child;child mental health service;Clinic;Color;Communities;Concise-Cap-C-Rynge;Consult;data management;design;Ethnicity aspects;experience;Faculty;Family;Health Personnel;Health Policy;Health Services Research;human subject protection;inner city;innovation;Mental Health;Mental Health Services;Mentors;Minority;Monitor;next generation;operation;Parents;Policy Maker;Poverty;Process;Provider;Psyche structure;Psychosocial Stress;public health medicine (field);Published Comment;Race;Research;Research Methodology;Research Personnel;Resources;response;Services;System;Testing;Training;Youth","PROJECT_TITLE":"Operations Core","SERIAL_NUMBER":"85983","STUDY_SECTION":"ZMH1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"5445","SUFFIX":"","SUPPORT_YEAR":"5","TOTAL_COST":"","TOTAL_COST_SUB_PROJECT":"387764"}
{"APPLICATION_ID":"8729690","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): This is a competitive renewal application to study the role an atypical homeodomain protein called Hopx that is expressed in the heart. My laboratory discovered Hopx about 10 years ago, and we have shown that it functions, at least in part, by recruiting histone deacetylases (HDACs) to transcription complexes. This work, funded by this grant, led to numerous high-profile publications, patent applications, and it has spurred our efforts in collaboration with the private sector to translate the findings and bring new therapies for heart failure to the clinic. Our mechanistic studies have shown that Hopx does not bind directly to DNA, but that it is a component of cardiac repressor complexes. Hopx is expressed by cardiac progenitor cells at early time-points of murine embryogenesis, just after Nkx2-5, at ~E8.0, and inactivation of Hopx leads to partially penetrant embryonic lethality and thin myocardium. Cardiac progenitors that express Nkx2-5 are multipotent and can produce myocardial, smooth muscle or endothelial lineages. However, Hopx-expressing progenitors are committed to the myocardial lineage. Our data suggest that fate decisions of cardiac precursor cells are biased by Hopx dose and activity. We hypothesize that Hopx is an extremely early (perhaps the earliest) marker of committed myocardial cells and that Hopx functions to reinforce the myocardial lineage choice by recruiting HDACs and other transcription cofactors to repress critical mediators of alternate fates and of the multipotent state. Understanding how myocardial fate decisions are executed and reinforced will inform our ability to enhance regenerative therapies and instruct stem and progenitor cells to produce functional myocardium.         ","ACTIVITY":"R01","ADMINISTERING_IC":"HL","APPLICATION_TYPE":"2","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"04/08/2014","BUDGET_START":"04/10/2014","BUDGET_END":"03/31/2015","CFDA_CODE":"837","CORE_PROJECT_NUM":"R01HL071546","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"PA-11-260","FULL_PROJECT_NUM":"2R01HL071546-10","FUNDING_ICs":"NHLBI:394588\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL HEART, LUNG, AND BLOOD INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"PHILADELPHIA","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"ANATOMY/CELL BIOLOGY","ORG_DISTRICT":"02","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF PENNSYLVANIA","ORG_STATE":"PA","ORG_ZIPCODE":"191046205","PHR":"PUBLIC HEALTH RELEVANCE: This project focuses on the regulation of expansion and differentiation of cardiac progenitor cells, which produce many of the cell types found in the adult heart including cardiac myocytes, smooth muscle and endothelial cells. The discovery of mechanisms to regulate expansion and differentiation of cardiac progenitor cells will enhance our ability to promote regenerative therapies for heart failure and heart attack patients.            ","PI_IDS":"1876674;","PI_NAMEs":"EPSTEIN, JONATHAN A;","PROGRAM_OFFICER_NAME":"SCHRAMM, CHARLENE A.","PROJECT_START":"09/01/2003","PROJECT_END":"03/31/2018","PROJECT_TERMS":"adapter protein;Adult;Alleles;alpha helix;Amino Acids;Animals;Binding (Molecular Function);Biochemical;Brain;Cardiac;Cardiac Myocytes;cell type;Cells;Chip seq;Clinic;Clustered Regularly Interspaced Short Palindromic Repeats;cofactor;Collaborations;Commit;Complex;Data;Development;DNA;Dose;Embryo;Embryonic Development;Endothelial Cells;Enhancers;Epitopes;Funding;Genes;Genetic Transcription;Genomics;Grant;Hair follicle structure;Heart;Heart failure;Helix-Turn-Helix Motifs;Histone Acetylation;Histones;Homeobox Genes;homeodomain;Homeodomain Proteins;Human;In Vitro;in vivo;induced pluripotent stem cell;Intestines;Laboratories;Legal patent;loss of function;Mediator of activation protein;Methylation;multipotent cell;Multipotent Stem Cells;Mus;Muscle Cells;Myocardial;Myocardial Infarction;Myocardial rupture;Myocardium;novel;Patients;Phenotype;Population;precursor cell;Pregnancy;Private Sector;progenitor;protein complex;public health relevance;Publications;Recruitment Activity;regenerative therapy;Regulation;Relative (related person);Role;Rupture;Site;Smooth muscle (tissue);Smooth Muscle Myocytes;Sorting - Cell Movement;Staging;stem;stem cell population;Stem cells;Structure;Technology;Testing;Time;Tissues;Tomatoes;Translating;Translations;Work","PROJECT_TITLE":"Analysis of a Novel Homeobox gene in CV Development","SERIAL_NUMBER":"71546","STUDY_SECTION":"ZRG1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"10","TOTAL_COST":"394588","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8605301","ABSTRACT_TEXT":" ABSTRACT: The human infant is typically sterile in utero and then born into a world dominated by microbes, which selectively assume residence of the body surfaces and enteric tract of the newborn. The assembly of the early human microbiome is particularly an issue relevant to the very low birth weight (VLBW;<1500 g) infant, where infection and activation of immunological and inflammatory responses produce acute morbidity and mor- tality and exacerbate co-morbid diseases of the eyes, enteric tract, and central nervous system. However, the selective forces that alter primary colonization and secondary persistence of more or less pathogenic microbes within the developing microbiota are not well understood, particularly in humans. Specifically, the extent to which colonization is recognized by the adaptive immune response and how the adaptive responses contribute to shaping the microbiome of the premature infant, and how the microbiome influences concurrent and subse- quent adaptive immune development, is poorly understood. The immediate goal of the proposed research is to identify antigens from the pioneering microbiome of the intestine in the preterm infant that are recognized by natural birth antibodies and the adaptive humoral response. This work will then determine whether and how the peripheral and mucosal antibody response alters the dynamics of secondary colonization. The central hypoth- esis is that natural antibodies present at birth modify primary colonization while antigens of pioneering Gram negative enteric bacteria drive adaptive antibody responses that alter secondary colonization and long-term immune memory. The hypothesis will be addressed through an innovative combination of molecular tools in the following aims: 1) To determine the relationship between natural and adaptive antibodies and colonization of the VLBW infant intestinal tract, 2) To determine the specificity of breast milk IgA to the breast milk microbi- ome and the early intestinal microbiome in the VLBW infant, and 3) To measure the specific antigens of the neonatal microbiome recognized by antibodies in the first year of life. These studies will uniquely define the constellation of antigens recognized by preterm infant and maternal natural and adaptive antibodies as the in- fant becomes colonized. By determining the dynamic interface between mucosal antibody response and spe- cific antigens recognized by the newborn human host, new interventions may be envisioned through which to alter primary and secondary colonization of infants through stimulation of natural and adaptive antibodies. In turn these advents may lead to approaches to alter long-term outcomes including infectious diseases, allergy, and metabolic syndrome.","ACTIVITY":"R01","ADMINISTERING_IC":"GM","APPLICATION_TYPE":"1","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"03/15/2014","BUDGET_START":"03/15/2014","BUDGET_END":"12/31/2014","CFDA_CODE":"859","CORE_PROJECT_NUM":"R01GM108494","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"RFA-GM-14-001","FULL_PROJECT_NUM":"1R01GM108494-01","FUNDING_ICs":"NIGMS:353250\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES","NIH_SPENDING_CATS":"","ORG_CITY":"DURHAM","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"PEDIATRICS","ORG_DISTRICT":"01","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"DUKE UNIVERSITY","ORG_STATE":"NC","ORG_ZIPCODE":"277054673","PHR":"PUBLIC HEALTH RELEVANCE: Recognition of colonizing microbes by the immune system following birth will have lasting consequences for the risk of infection, allergy, and metabolism. Premature infants are particularly at risk of these health problems, in the short term, in the form of bronchopulmonary dysplasia, necrotizing enterocolitis, and sepsis, and in the longer term, disorders of allergy, metabolism, and susceptibility to infectious diseases. Understanding immune recognition of microbial colonization may provide new insights into how to improve immunity and decrease future health problems.                ","PI_IDS":"8506614;","PI_NAMEs":"SEED, PATRICK C.;","PROGRAM_OFFICER_NAME":"SLEDJESKI, DARREN D.","PROJECT_START":"03/15/2014","PROJECT_END":"12/31/2017","PROJECT_TERMS":"Acute;Acute Disease;Address;Affect;Age;Antibodies;Antibody Formation;Antigens;B-Lymphocyte Subsets;Biological Assay;Birth;Body Surface;Breast;Bronchopulmonary Dysplasia;Child;Chronic Disease;Communicable Diseases;Complementary DNA;Data;Development;Disease;Diversity Library;DNA;DNA Sequence;Engineering;Enteral;Enterobacteriaceae;Environment;Enzyme-Linked Immunosorbent Assay;Event;Eye diseases;Feces;Future;Goals;Health;High-Throughput Nucleotide Sequencing;Human;Human Microbiome;Human Milk;Hypersensitivity;IgE;Immune;Immune response;Immune system;Immunity;Immunoglobulin A;Immunoglobulin G;Immunoglobulin M;Immunoglobulins;improved;in utero;Infant;Infection;Inflammatory Response;innovation;insight;Intervention;Intestines;Knowledge;Lead;Libraries;Life;Maps;Measures;Memory;Memory B-Lymphocyte;Metabolic syndrome;Metabolism;Metagenomics;Microbe;microbial;microbial colonization;microbiome;microorganism;Molecular;Morbidity - disease rate;Mortality Vital Statistics;MS4A1 gene;Necrotizing Enterocolitis;Neonatal;Neuraxis;Newborn Infant;next generation;next generation sequencing;Organism;Outcome;Peripheral;Phage Display;Predisposition;Premature Infant;public health relevance;Research;residence;response;Risk;Role;Secretory Immunoglobulin A;Sepsis;Serological;Shapes;Specificity;Staphylococcaceae;Sterility;tool;Very Low Birth Weight Infant;Work","PROJECT_TITLE":"MICROBIAL SUCCESSION AND ADAPTIVE IMMUNE RESPONSES IN THE PREMATURE INFANT","SERIAL_NUMBER":"108494","STUDY_SECTION":"ZGM1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"1","TOTAL_COST":"353250","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8709837","ABSTRACT_TEXT":" Virini Dprtmntof AgriultreadCnumrServie AdvnigCnfrmne wit   teVlntryNtinl RtilFo RgultoryPrgramStnars PrjctSmmry/Prpsl Astrct TeVirgii Dprtmnt ofAgricltur nd CnsumrSrvics (DC)is sekingfnig from teU.S.Fo nd DrgAmiistrtinudrRA -D -2-1 tosuprttedprtmnt's cnfrmncewit teVolntryNtinlRtilFo RglatryPrormStnards (VNRRPS). h amutof fnigreqestdis$5,00. TeFo ndDru Amiistrtin (DA), Office ofRegltoryAffirs(ORA), ivsonof eerl-Stat Rltins (DSR) n teCnter forFodSafetyadAplidNtritin(CSAN), isanucigteavilailityofcoertiv agremntstobeawre nerLimitd Cmetitin. Tisoprtnityisolyavilbl t Stt,lcl,territoril,or trialretil fod regltryproramswit rimaryregltoryrsosiilityfor retil fo estblismnts tatare crrntlyerlldi te VNRRPSadhv cmltdacurrntsl-sf sssmnt agistte RtilProgramStnardsas reqirdbyStnar . TeVDACSOffic ofDairy...Fos,Fo Safety...ScrityProgram metsall reqirmntsto e ligil fortisfnig. Te programsrvsas n oftte[unreadable]ssptarimryretil fod regltryproramsadiscurrntlyerlldi th VNRRPS. Teprorm'sls- tslf asesment agist te RtilProgramStnards s reqirdbyStnar  wscmletdon Mrc 1,212. Avrifictinaditwscmltdo Jne2,212 ndcnfirmdtat te rogramdes metStnar 7 - IdstryadCommnityRltins. udigprvie yte RAwillb tilizdt cntiu teprorm'scnfrmnc wit te VRFPS b imlmntigprcdres tatpromt ctiv mnagril cotrl ofterisk fctors mstcommnlyasscitdwit foboreillessi fodestblishmnts. Secificlly te fnigwillb sdt metStnard2 -Trie RglatryStaff- by aloingthe rogram t irea aditinlemlyetatwul e rsosil forStnarizigadRe- Stnarizig fodisectinstaffwiti te requirdtimeframsasotlie i teStna r. I ditin tispersnwul ersonsil frdraftigadimlmntin rcdurs tat wul nac teprorm 'sailityt cnfrmwit Stnar 3I-sectinProgramBsdon HACCPPricils;Stnar 4 -UiformIspctinProgram;Stnar 6 -Comlinc n  Eforcemnt;ad Stndr 8 -ProramSportadRsurcs .","ACTIVITY":"U18","ADMINISTERING_IC":"FD","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"06/25/2014","BUDGET_START":"07/01/2014","BUDGET_END":"06/30/2015","CFDA_CODE":"","CORE_PROJECT_NUM":"U18FD004667","ED_INST_TYPE":"","FOA_NUMBER":"RFA-FD-12-011","FULL_PROJECT_NUM":"5U18FD004667-03","FUNDING_ICs":"","FUNDING_MECHANISM":"Other Research Related","FY":"2014","IC_NAME":"FOOD AND DRUG ADMINISTRATION","NIH_SPENDING_CATS":"","ORG_CITY":"RICHMOND","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"03","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"VA ST DEPT/ AGRICULTURE &CONSUMER SRVS","ORG_STATE":"VA","ORG_ZIPCODE":"232193676","PHR":" Virini Dprtmntof AgriultreadCnumrServie AdvnigCnfrmne wit   teVlntryNtinl RtilFo RgultoryPrgramStnars PrjctNrrative udigprvie t sportteVirgii DprtmntofAricltreadCosmr Srvics odSafety...Scrity Prgrmwillb sdto nac teprorami evlpig, imlmnting,adimrovigteinfrstrctrenecssrytosportcnformncewit te VlntryNtinlRtilFo RegltoryProgramStnars. Tislwtl regthe th  prtinadmnagmntof te rtil fo prorms tatitis fcsd nterdctinof risk fctors kow t cus rcntriuteto fobreillessadpromteteactiv mnageril cntrlof teserisk fctors. ","PI_IDS":"10079572;","PI_NAMEs":"MILES, PAMELA W;","PROGRAM_OFFICER_NAME":"","PROJECT_START":"09/12/2012","PROJECT_END":"06/30/2017","PROJECT_TERMS":"","PROJECT_TITLE":"Virginia Department of Agriculture and Consumer Services Advancing Conformance wi","SERIAL_NUMBER":"4667","STUDY_SECTION":"ZFD1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"3","TOTAL_COST":"","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8701176","ABSTRACT_TEXT":"Clostridium difficile is a toxin-producing bacterium that is a frequent cause of hospital-acquired and  antibiotic-associated diarrhea. The incidence and severity of C. difficile infection (CDI) are increasing, in parallel with increases in community-acquired infections, making CDI a major public health problem.  Following inoculation, patients may clear C. difficile from their intestinal tract, become asymptomatically colonized, or develop CDI, ranging in severity from mild diarrhea to fulminant colitis and/or death. Older adults are disproportionately affected by CDI, experiencing greater morbidity and mortality. Antibiotics treat CDI, but refractory disease and relapses occur. Major gaps exist in our understanding ofthe host and microbial factors that determine the outcome of human contact with C. difficile. The broad objective of this ERIN CRC is to develop innovative approaches to the diagnosis, prevention, and treatment of CDI based on understanding the molecular mechanisms of disease. The goals of this Proiect are to use genomic information obtained from clinical C. difficile strains, to identify microbial determinants of infection and develop a rapid, high-throughput assay to predict the clinical behavior of individual C. difficile strains. We hypothesize that there is a genomic basis for the different clinical presentations of C. difficile (colonization, mild or severe infection, and relapse) in susceptible hosts. The Specific Aims of this  proposal seek to: (1) Establish a collection of isolates that spans the genetic diversity of C. difficile  associated with both asymptomatically colonized adults and those with initial and recurrent infection;(2) Perform a comparative phylogenomic analysis of representative C. difficile isolates obtained from Aim 1;and (3) Develop a high-throughput single nucleotide polymorphism (SNP) typing system for the rapid discrimination and risk-assessment ofC. difficile infection. This project will collect clinicoepidemiological data, biological specimens and C. difficile strains, which will be used in all three major projects of this ERIN.","ACTIVITY":"U19","ADMINISTERING_IC":"AI","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"07/23/2014","BUDGET_START":"08/01/2014","BUDGET_END":"07/31/2015","CFDA_CODE":"","CORE_PROJECT_NUM":"U19AI090871","ED_INST_TYPE":"","FOA_NUMBER":"RFA-AI-09-023","FULL_PROJECT_NUM":"5U19AI090871-05","FUNDING_ICs":"NIAID:371916\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES","NIH_SPENDING_CATS":"","ORG_CITY":"ANN ARBOR","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"12","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF MICHIGAN","ORG_STATE":"MI","ORG_ZIPCODE":"481091274","PHR":"Clostridium difficile is a common cause of antibiotic-associated and hospital-associated diarrhea. It is an emerging pathogen that is highly transmissible and opportunistic, imposing a significant burden on global health and healthcare resources. The best method to control the spread of CDI is to better understand its pathogenesis. These studies will provide an important foundation for developing more accurate diagnostic, preventive, and therapeutic regimens against this important problem.","PI_IDS":"6665047;","PI_NAMEs":"ARONOFF, DAVID M;","PROGRAM_OFFICER_NAME":"","PROJECT_START":"","PROJECT_END":"","PROJECT_TERMS":"Acute;Adult;Affect;Anaerobic Bacteria;Antibiotics;Bacteria;base;Behavior;Biological;Cessation of life;Clinical;clinically relevant;Clostridium difficile;Colitis;Collection;Community-Acquired Infections;comparative;Cytotoxin;Data;Diagnosis;Diagnostic;Diarrhea;Discrimination (Psychology);Disease;Elderly;Epidemic;Epidemiology;experience;Foundations;Genetic;genetic analysis;Genetic Determinism;genome sequencing;Genomics;global health;Goals;Healthcare;high throughput screening;Hospitals;Human;Incidence;Individual;Infection;innovation;Intestines;Methods;microbial;microbial host;Modeling;Molecular;Morbidity - disease rate;Mortality Vital Statistics;Outcome;pathogen;Pathogenesis;patient population;Patients;Phylogenetic Analysis;Population Genetics;Prevention;Preventive;public health medicine (field);Recurrence;Refractory Disease;Regimen;Relapse;Research;Resources;Risk Assessment;Severities;Single Nucleotide Polymorphism;Specimen;System;Testing;Therapeutic;tool;Toxin;Variation (Genetics)","PROJECT_TITLE":"Epidemiology and Genomics of Clostridium difficile","SERIAL_NUMBER":"90871","STUDY_SECTION":"ZAI1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"7536","SUFFIX":"","SUPPORT_YEAR":"5","TOTAL_COST":"","TOTAL_COST_SUB_PROJECT":"371916"}
{"APPLICATION_ID":"8832003","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): Currently, approximately 7 million Americans use hearing aid devices, which usually use compact Zn-air batteries. These batteries are relatively inexpensive, safe to use, and easy to dispose of, but only work for approximately 1 week before needing to be replaced. Practically all other modern gadgets (cell phones, computers, etc.) now utilize rechargeable lithium-ion (Li-ion) batteries, which have lower charge capacity and need frequent (practically daily) recharging. Although frequent recharging may be acceptable for gadget users, it may create potentially a life threating situation for users of medical devices. Th frequent need to replace or recharge hearing aid batteries creates a logistical problem for users, especially for seniors, who constitute the largest segment of hearing aid users. In response to the NIH National Institute on Deafness and Other Communication Disorders (NIDCD) request for new rechargeable batteries for hearing aid devices, Physical Optics Corporation (POC) proposes to develop a new High-Capacity Li-ion Rechargeable (HCLIR) battery. The significant (fourfold) increase in the battery capacity, compare to the current capacity of Li-ion batteries wil be achieved with a new silicon (Si) microporous anode. Si has an outstanding lithium (Li) insertion capacity, which is 10 times higher than conventional graphite, but suffers from large volume changes while absorbing and releasing Li. The proposed anode structure not only significantly increases surface area available for the reaction with Li, but also permits material extension, thus allowing for multiple charge/discharge cycles. As a result of this innovation, the proposed compact battery (size A312) will be capable of storing energy sufficient for approximately 1 week of hearing aid operation without recharging. Users will be able to recharge the battery using the same (or similar) charger they use for their cell phones and other gadgets, with an additional compartment for a small size battery. The cost of the proposed battery will be completely recovered after several months of use, while its service life will be several years long. In Phase I, POC will demonstrate the feasibility of the proposed A312 size battery with a Si microporous anode by optimizing the battery design, fabricating battery prototypes, measuring their capacity, and demonstrating their capability to withstand multiple charge/discharge cycles. In Phase II, POC will optimize the manufacturing technology to reduce battery cost. We will also certify the developed battery according to ANSI/IEC requirements. Successful accomplishment of the proposed development will directly benefit millions of hearing aid users. The proposed technology can be modified easily for use in other medical devices and for a broad commercial market for numerous electronic devices which utilize Li-ion batteries.        ","ACTIVITY":"R43","ADMINISTERING_IC":"DC","APPLICATION_TYPE":"1","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"09/16/2014","BUDGET_START":"09/16/2014","BUDGET_END":"03/31/2015","CFDA_CODE":"173","CORE_PROJECT_NUM":"R43DC014373","ED_INST_TYPE":"","FOA_NUMBER":"PA-14-071","FULL_PROJECT_NUM":"1R43DC014373-01","FUNDING_ICs":"NIDCD:149999\\","FUNDING_MECHANISM":"SBIR-STTR","FY":"2014","IC_NAME":"NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS","NIH_SPENDING_CATS":"","ORG_CITY":"TORRANCE","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"43","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"PHYSICAL OPTICS CORPORATION","ORG_STATE":"CA","ORG_ZIPCODE":"905011821","PHR":"PUBLIC HEALTH RELEVANCE: The proposed development will result in significant enhancement of the charge capacity of rechargeable Li-ion batteries, thus making possible their use in modern hearing aid devices. Over 7 million Americans will benefit from the elimination of the logistical burden associated with frequent battery replacement or recharging, while saving ~$100 over two years of use of the proposed battery.            ","PI_IDS":"1875209;","PI_NAMEs":"SHNITSER, PAUL;","PROGRAM_OFFICER_NAME":"MILLER, ROGER ","PROJECT_START":"09/16/2014","PROJECT_END":"03/31/2015","PROJECT_TERMS":"Adult;Air;American;Anodes;Area;base;Cellular Phone;Charge;Cochlear Implants;Computers;Cosmetics;cost;design;Development;Devices;Dimensions;Electronics;Evaluation;experience;flexibility;Goals;Government;Hearing Aids;hearing impairment;improved;innovation;Investigation;Ions;Life;Lithium;Marketing;Measures;Medical Device;Medical Technology;nano;Nanotubes;nanowire;National Institute on Deafness and Other Communication Disorders;Natural graphite;novel;operation;Optics;Persons;Phase;prevent;Price;prototype;public health relevance;Reaction;Relative (related person);Reporting;Research;response;Semiconductors;Services;Shapes;Silicon;social stigma;sound;Structure;Surface;Technology;Thick;Time;United States National Institutes of Health;Work","PROJECT_TITLE":"High-Capacity Li-Ion Rechargeable Battery","SERIAL_NUMBER":"14373","STUDY_SECTION":"ZRG1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"1","TOTAL_COST":"149999","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8757072","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): This is the amended competing renewal application of the Study of Women's Health Across the Nation (SWAN), a 7-site longitudinal cohort study initiated in 1994 in response to RFA AG-94-002. SWAN was mandated \"to characterize the chronology of the biological and psychosocial antecedents and sequelae of the menopausal transition (MT) and the effect of this transition on subsequent health and risk factors for age- related disease\", and to extend this information from White women to \"...the range of peri-menopausal experiences in women of other racial/ethnic background(s).\" A total of 3302 Black, Chinese, Japanese, Hispanic and White women were enrolled, with 78% completing up to 13 visits spanning the premenopause to early post-menopause (PM). Thus far, SWAN has described the natural history of the MT -- its timing, patterns of hormonal changes, and symptoms and factors related to them - and their relation to disease risk indicators. During SWAN V, we will extend observations through the late PM, a necessary step to assess the impact of the MT on age-related diseases. Our specific aims are to: 1) complete the characterization of the natural history of reproductive aging through the late PM;2) evaluate the impact of reproductive aging through the late PM on health outcomes clinically relevant to women in their 60s and 70s, including: cognitive and physical function, psychological well-being, sleep, bone and cardiometabolic health, urogenital symptoms, sexual function and vaginal health;and 3) identify potential underlying mechanisms linking reproductive aging and health by assessing the relation of inflammation, hemostasis and adipokines to the occurrence and progression of biological, functional and clinical outcomes and delineating the interrelationships of body size and composition, race/ethnicity and socioeconomic status with these outcomes. The SWAN V Core protocol will be completed at 7 study sites, with bone and cardiovascular studies at 4 sites and actigraphy studies in a subset of women at all sites. Longitudinal specimens from the SWAN Repository will enable characterization of skeletal markers, adrenal hormones, hemostasis, inflammation, and adipokines across the MT into PM. The Coordinating Center will provide the necessary organizational infrastructure, statistical resources, and timely dissemination of high quality SWAN data. The CLIA-certified Central Laboratory will perform or coordinate with other laboratories to provide accurate, high volume assays, adopting new methods as needed to provide state- of-the-art data. SWAN is uniquely positioned to fill important scientific gaps in understanding of the impact of the MT on women's health in their 60s and 70s and to facilitate the application of new knowledge to clinical practice. With 1.5 decades of both calendar time and \"menopause time\", SWAN V can disaggregate the contributions of aging and the MT to women's health, address difficult and critical questions about the temporal nature of MT-disease associations, assess differences by race/ethnicity, and provide insights into modifiable factors relevant to the design of innovative prevention and treatment programs for aging women.        ","ACTIVITY":"U01","ADMINISTERING_IC":"AG","APPLICATION_TYPE":"2","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"09/08/2014","BUDGET_START":"09/15/2014","BUDGET_END":"06/30/2015","CFDA_CODE":"866","CORE_PROJECT_NUM":"U01AG012505","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"PAR-13-097","FULL_PROJECT_NUM":"2U01AG012505-21A1","FUNDING_ICs":"NIA:700848\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE ON AGING","NIH_SPENDING_CATS":"","ORG_CITY":"CHICAGO","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"PSYCHIATRY","ORG_DISTRICT":"07","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"RUSH UNIVERSITY MEDICAL CENTER","ORG_STATE":"IL","ORG_ZIPCODE":"606123833","PHR":"PUBLIC HEALTH RELEVANCE: SWAN will fill important gaps in understanding the impact of the menopausal transition and mid-life aging on women's health and functioning in the postmenopausal years. Accordingly, it will provide useful information to guide clinical decisions in mid-life and beyond in women who have diverse life experiences and socioeconomic and racial/ethnic characteristics.            ","PI_IDS":"3052938;","PI_NAMEs":"KRAVITZ, HOWARD M;","PROGRAM_OFFICER_NAME":"ROSSI, WINIFRED K.","PROJECT_START":"09/30/1994","PROJECT_END":"06/30/2019","PROJECT_TERMS":"actigraphy;Address;adipokines;Adopted;Adrenal Glands;Adrenal hormone preparation;Age;age related;Aging;Androstenediols;Biological;Biological Assay;Biology;Body Composition;Body mass index;Body Size;bone;Bone Density;Calendar;Cardiovascular Diseases;Cardiovascular system;Cessation of life;Characteristics;Charge;Chicago;Chinese People;Chronology;Clinical;clinical practice;clinically relevant;cognitive function;cohort;Cohort Studies;Data;Data Collection;dehydroepiandrosterone;Dehydroepiandrosterone Sulfate;design;Disease;Disease Association;Disease Outcome;disorder risk;Enrollment;Estradiol;Ethnic group;Ethnicity aspects;Event;experience;Follicle Stimulating Hormone;follow-up;Fracture;functional outcomes;Genitourinary system;Gonadal Steroid Hormones;Health;Hemostatic function;Hispanics;Hormonal Change;hormone binding protein;Hormones;Inflammation;Inflammatory;innovation;insight;Japanese Population;Knowledge;Laboratories;Life Experience;Link;Measures;Mediator of activation protein;Menopause;Menstruation;Methods;middle age;Mission;Moods;Natural History;Nature;Outcome;Ovarian;Pattern;Personal Satisfaction;Physical Function;Physiological;Physiology;Positioning Attribute;Postmenopause;Premenopause;Prevention program;Protocols documentation;psychologic;psychosocial;public health relevance;Race;racial and ethnic;racial difference;racial/ethnic difference;Recording of previous events;repository;reproductive;Research Infrastructure;Resources;response;Risk;Risk Factors;Sex Functioning;Sex Hormone-Binding Globulin;Shapes;Signal Transduction;Site;skeletal;Sleep;social;Socioeconomic Status;socioeconomics;Specimen;Steroids;Symptoms;Testosterone;Time;Time Study;treatment program;Vagina;Variant;Vasomotor;Visit;Woman;Women's Health;Work","PROJECT_TITLE":"Study of Women's Health Across the Nation (SWAN) V: Chicago site","SERIAL_NUMBER":"12505","STUDY_SECTION":"ZAG1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"A1","SUPPORT_YEAR":"21","TOTAL_COST":"700848","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8695864","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): The basic concept of personalized medicine is to tailor the treatment for a patient based on his or her genetic makeup, clinical conditions and other personal characteristics to improve efficacy and safety. The coming of the big data era enables us to characterize individual in fine pictures and make the \"personalized\" clinical decision truly personalized. Such an approach has great potential for improving disease prevention, diagnosis and treatment. For example, in a typical randomized clinical trial aiming for proving the efficacy of a treatment, the final conclusion is drawn based on the average treatment effect in the entire study population. It is possible that while the average treatment effect is near null, the treatment may still be beneficial to a subgroup of patients whose identification prior to the treatment is thus very important. The overall objective of statistical analysis in this area is to provide a data-based empirical estimator for the personalized treatment effect, which can be used to identify subgroup of patients who may benefit the most from a treatment. In this study, we first propose to develop robust statistical methods for estimating the group-specific treatment effect. The proposed approach incorporating many existing methods as special cases depends on minimum model assumptions and provides a general framework for generalization and improvement. We will also discuss how to use the estimated personalized treatment effect to stratify patient population into clinically meaningful strata for better assisting the decision making of clinicians. Secondly, we will study a regularize principal components analysis method for dimension reduction in structured high-dimensional data. The output from the analysis can be used to summarize the characteristics of individual patient as well as for predicting future clinical outcomes of interest. Multiple methods can be used to estimate the treatment effect and form the corresponding treatment selection strategy. Therefore it is important to evaluate and compare the performance of such strategies. Thus our last aim is to develop a systematic robust procedure for evaluating the performance of the personalized treatment effect estimation and associated treatment selection strategy.        ","ACTIVITY":"R01","ADMINISTERING_IC":"HL","APPLICATION_TYPE":"2","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"03/12/2014","BUDGET_START":"04/01/2014","BUDGET_END":"03/31/2015","CFDA_CODE":"837","CORE_PROJECT_NUM":"R01HL089778","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"PA-11-260","FULL_PROJECT_NUM":"2R01HL089778-05","FUNDING_ICs":"NHLBI:256609\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL HEART, LUNG, AND BLOOD INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"STANFORD","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"MISCELLANEOUS","ORG_DISTRICT":"18","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"STANFORD UNIVERSITY","ORG_STATE":"CA","ORG_ZIPCODE":"943041222","PHR":"PUBLIC HEALTH RELEVANCE: For a given treatment, the effect may be very different for different patients. Therefore it is important to develop methods predicting the personalized treatment effect and discovering subgroup of patients who may benefit from a treatment. In this proposal, we plan to study the statistical methods to help achieve these important goals by analyzing empirical data.            ","PI_IDS":"8247689;","PI_NAMEs":"TIAN, LU;","PROGRAM_OFFICER_NAME":"WOLZ, MICHAEL ","PROJECT_START":"07/01/2007","PROJECT_END":"03/31/2018","PROJECT_TERMS":"Area;base;Big Data;Characteristics;Clinical;Clinical assessments;clinical practice;Complex;cost;Data;Databases;Decision Making;Diagnosis;Dimensions;Disease;Disease Management;disorder prevention;Effectiveness;Ensure;Evaluation;Event;Future;Genetic;Genetic screening method;Goals;Human Genome Project;improved;Individual;interest;Measures;Medical Research;Medicine;Methods;Modeling;Outcome;Output;patient population;Patients;Performance;population based;Population Study;Prevention;Principal Component Analysis;Procedures;Process;public health relevance;Randomized Clinical Trials;Risk;Safety;Selection for Treatments;Statistical Methods;Structure;Subgroup;System;tool;treatment effect;treatment response;Validation","PROJECT_TITLE":"Statistical Methods for Optimizing Personalized Treatment Selection","SERIAL_NUMBER":"89778","STUDY_SECTION":"BMRD","STUDY_SECTION_NAME":"Biostatistical Methods and Research Design Study Section","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"5","TOTAL_COST":"256609","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8634111","ABSTRACT_TEXT":"Phosphonic acids are a potent, yet underexploited, group of compounds with great promise in the treatment of  human disease. Numerous structurally distinct phosphonates are produced in nature and many have useful  bioactive properties. Importantly, the biological targets of phosphonic acids vary substantially, allowing them to  be used for treating a variety of health conditions. The potent bioactivity of phosphonates also allows their use  as fungicides, herbicides and pesticides. In our Initial funding period we showed that phosphonate biosynthesis  is surprisingly common in nature and that a wealth of uncharacterized natural products await characterization.  In this sub-project we propose a series of molecular, genetic and biochemical experiments aimed at exploiting  and expanding these discoveries.","ACTIVITY":"P01","ADMINISTERING_IC":"GM","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"03/27/2014","BUDGET_START":"04/01/2014","BUDGET_END":"03/31/2015","CFDA_CODE":"","CORE_PROJECT_NUM":"P01GM077596","ED_INST_TYPE":"","FOA_NUMBER":"PAR-10-266","FULL_PROJECT_NUM":"5P01GM077596-08","FUNDING_ICs":"NIGMS:422754\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES","NIH_SPENDING_CATS":"","ORG_CITY":"CHAMPAIGN","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"13","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF ILLINOIS URBANA-CHAMPAIGN","ORG_STATE":"IL","ORG_ZIPCODE":"618207406","PHR":"","PI_IDS":"1965444;","PI_NAMEs":"METCALF, WILLIAM W.;","PROGRAM_OFFICER_NAME":"","PROJECT_START":"","PROJECT_END":"","PROJECT_TERMS":"Actinobacteria class;Address;Anabolism;Antibiotic Resistance;Antibiotics;antimicrobial;Bacillus (bacterium);Biochemical;Bioinformatics;Biological;Biological Assay;Biological Factors;Chemicals;Coculture Techniques;Corynebacterium glutamicum;cost;Data;design;Development;Dose;Enzymes;Exposure to;feeding;Funding;Gene Cluster;Genes;Genetic;genome sequencing;Genomics;Goals;Gram-Positive Bacteria;Growth;Health;Herbicides;human disease;improved;Individual;Industrial fungicide;Knowledge;Lesion;Metabolic Pathway;Methods;microbial;microorganism;Molecular;Molecular Genetics;mutant;Nature;novel;overexpression;Pathway interactions;Pesticides;phosphonate;Phosphonic Acids;Phylogenetic Analysis;Production;programs;Property;Proteobacteria;Pseudomonas aeruginosa;Regulator Genes;Research;research study;screening;Series;Source;Staging;Streptomyces;synthetic biology;System","PROJECT_TITLE":"PHOSPHONIC ACID BIOSYNTHETIC PATHWAYS","SERIAL_NUMBER":"77596","STUDY_SECTION":"ZRG1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"8254","SUFFIX":"","SUPPORT_YEAR":"8","TOTAL_COST":"","TOTAL_COST_SUB_PROJECT":"422754"}
{"APPLICATION_ID":"8777693","ABSTRACT_TEXT":"DESCRIPTION provided by applicant -Lactamase-mediated bacterial resistance continues to evolve toward a broader substrate spectrum, including the most potent -lactam antibiotics, the carbapenems. New carbapenemases include both serine hydrolases, such as the class A KPC -lactamases, as well as the class B metallo--lactamases MBLs, such as NDM-1, which has spread globally since its appearance just five years ago. This project will prepare and evaluate atypically substituted bicyclic -lactams, including both carbapenems and penams, to assess the potential to further develop these -lactam scaffolds as poor substrates andor inhibitors of the MBLs. The project is guided by recent structural data on acyl-enzymes of key penicillin-binding proteins PBPs, particularly including PBP3 from Pseudomonas aeruginosa and Acinetobacter baumannii, as well as complexes of hydrolyzed antibiotics with the MBLs, particularly including complexes of NDM-1. The positions to be modified represent positions that have not been extensively examined, due to synthetic difficulty. Several collaborators including, Peter Oeschlaeger, Robert Bonomo, German Bou, and Natalie Strynadka will provide kinetic, microbiological, and structural information, respectively, on the interactions of the newly synthesized antibiotics and the MBLs.","ACTIVITY":"R15","ADMINISTERING_IC":"AI","APPLICATION_TYPE":"1","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"06/27/2014","BUDGET_START":"07/01/2014","BUDGET_END":"06/30/2017","CFDA_CODE":"855","CORE_PROJECT_NUM":"R15AI109624","ED_INST_TYPE":"SCHOOLS OF ARTS AND SCIENCES","FOA_NUMBER":"PA-13-313","FULL_PROJECT_NUM":"1R15AI109624-01A1","FUNDING_ICs":"NIAID:438212\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES","NIH_SPENDING_CATS":"","ORG_CITY":"DALLAS","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"CHEMISTRY","ORG_DISTRICT":"32","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"SOUTHERN METHODIST UNIVERSITY","ORG_STATE":"TX","ORG_ZIPCODE":"75205","PHR":"PUBLIC HEALTH RELEVANCE This project will utilize recently reported structural data to guide the synthesis of new -lactam antibiotics which are less susceptible to metallo--lactamases, enzymes which can hydrolyze nearly all current -lactam antibiotics. The strategy involves appending substituents at key positions, representing positions that have not been thoroughly examined. New synthetic chemistry has already been developed to facilitate this investigation.","PI_IDS":"1946886;","PI_NAMEs":"BUYNAK, JOHN D;","PROGRAM_OFFICER_NAME":"XU, ZUOYU ","PROJECT_START":"07/01/2014","PROJECT_END":"06/30/2017","PROJECT_TERMS":"Acinetobacter baumannii;Anti-Bacterial Agents;Antibiotics;Appearance;Area;Bacteria;bacterial resistance;base;beta-Lactamase;Bioavailable;Carbapenems;Clinical Trials;clinically relevant;Combined Antibiotics;Complex;Data;design;Development;Disadvantaged;Electronics;Enzymes;Evaluation;experience;Face;Future;German population;Goals;Health;Hydrolase;Hydrolysis;hydroxamate;improved;Incidence;inhibitor/antagonist;Investigation;Kinetics;Knowledge;Lactamase;Lactams;Mediating;member;Membrane;metalloenzyme;microorganism;Modification;Monobactams;pathogen;Penicillin-Binding Proteins;periplasm;Pharmaceutical Preparations;porin;Positioning Attribute;Predisposition;programs;Property;Proteins;Pseudomonas aeruginosa;Reporting;Resistance;Risk;scaffold;Series;Serine;Serine Hydrolase;Side;Site;Structure;Substrate Specificity;Sulfhydryl Compounds;Surface;Synthesis Chemistry;Variant;Zinc","PROJECT_TITLE":"Bicyclic beta-Lactam Antibiotics as Poor Substrates for Metallo-beta-lactamases","SERIAL_NUMBER":"109624","STUDY_SECTION":"ZRG1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"A1","SUPPORT_YEAR":"1","TOTAL_COST":"438212","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8640933","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): The modern world has experienced enormous growth in obesity, a disease associated with increased incidence of and mortality from diabetes, cardiovascular disease and cancer. Even moderate weight loss in the range of 5-10% has been shown to prevent the long-term consequences of obesity. Unfortunately, the current treatment options for obesity remain limited in both their application and effect.  Our preliminary data indicate that sarcolemmal ATP-sensitive K+ (KATP) channels limit muscle energy expenditure under physiological workload, while KATP channel deficit provokes an extra energy cost of muscle performance. Inefficient fuel metabolism in KATP channel-deficient muscles reduces body fat deposits promoting a lean phenotype. The current proposal builds on this finding to determine the mechanisms by which KATP channel function affects skeletal muscle performance, and adipose tissue mobilization.  We hypothesize that membrane potential modulation, due to KATP channel opening in response to a physiological workload, limits calcium and sodium inward currents and thus energy consumption related to ion homeostasis and contraction continuation. Under conditions of surplus calorie intake this promotes weight gain. Conversely, disruption of KATP channel function would result in exaggerated cellular calcium turnover, causing increased energy consumption and activation of calcium/calmodulin dependent protein kinase (Ca2+/CaMKII). We propose, that induction of CaMKII triggers both Akt-dependent production and Ca2+- dependent secretion of a signaling peptide - musclin. This peptide is known for its ability to modulate clearance of atrial natriuretic peptide (ANP) - a potet activator of lipolysis. In this way, musclin signaling could translate increased activity related energy consumption into adipose tissue mobilization. The goal of this project is to directly study the molecular mechanism of KATP channel control of activity- related energy consumption and the mechanism of consequent adipose tissue mobilization and body weight reduction.  The proposed investigation will be performed across multiple models - biochemical and electrophysiological studies on cellular and isolated organ levels will be used to verify molecular mechanisms for findings obtained on the whole body level. Understanding these mechanisms will provide novel avenues for targeted management and prevention of obesity and related diseases.        ","ACTIVITY":"R01","ADMINISTERING_IC":"DK","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"03/13/2014","BUDGET_START":"04/01/2014","BUDGET_END":"03/31/2015","CFDA_CODE":"847","CORE_PROJECT_NUM":"R01DK092412","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"PA-10-067","FULL_PROJECT_NUM":"5R01DK092412-03","FUNDING_ICs":"NIDDK:328425\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES","NIH_SPENDING_CATS":"","ORG_CITY":"IOWA CITY","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"INTERNAL MEDICINE/MEDICINE","ORG_DISTRICT":"02","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF IOWA","ORG_STATE":"IA","ORG_ZIPCODE":"52242","PHR":" Obesity is occurring at epidemic rates and has exceeded 30% of the U.S. population. Yet despite the medical, social and economic impact of obesity, only a few therapeutic options with limited success rates are currently available. This application addresses the novel hypotheses that metabolism-sensing KATP channels are important regulators of bodily energy balance and weight management, due to the effect of their function on muscle energy efficiency and mobilization of fat, and are potential targets for prevention and treatment of obesity.            ","PI_IDS":"9257190;","PI_NAMEs":"ZINGMAN, LEONID;","PROGRAM_OFFICER_NAME":"LAUGHLIN, MAREN R","PROJECT_START":"04/25/2012","PROJECT_END":"03/31/2017","PROJECT_TERMS":"Acute;Address;Adipose tissue;Affect;Area;Atrial Natriuretic Factor;base;Biochemical;biochemical model;Biology;Body fat;Body Weight;Body Weight decreased;Calcium;Calcium/calmodulin-dependent protein kinase;calmodulin-dependent protein kinase II;Cardiovascular Diseases;Consumption;cost;Data;Deposition;Diabetes Mellitus;Disease;Eating;economic impact;energy balance;Energy Metabolism;Epidemic;Equilibrium;Equipment;experience;Fatty acid glycerol esters;Food Energy;Functional disorder;Goals;Growth;Homeostasis;Incidence;inhibitor/antagonist;Intake;Investigation;Ions;Laboratories;Lipolysis;Malignant Neoplasms;Medical;Membrane;Membrane Potentials;Messenger RNA;Metabolism;Methods;Modeling;Molecular;Mortality Vital Statistics;mouse model;Mus;Muscle;Muscle Cells;novel;Obesity;Obesity associated disease;obesity treatment;Organ;Peptide Signal Sequences;Peptides;Performance;Phenotype;Physiological;Population;prevent;Prevention;Production;Proto-Oncogene Proteins c-akt;Publishing;Regulation;response;Role;Signal Transduction;Skeletal muscle structure;Social Impacts;Sodium;success;Therapeutic;Transgenic Mice;Translating;Translations;Weight Gain;Weight maintenance regimen;Workload","PROJECT_TITLE":"Skeletal muscle KATP channels determine bodily energy balance","SERIAL_NUMBER":"92412","STUDY_SECTION":"SMEP","STUDY_SECTION_NAME":"Skeletal Muscle Biology and Exercise Physiology Study Section","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"3","TOTAL_COST":"328425","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8675250","ABSTRACT_TEXT":"   DESCRIPTION (provided by applicant): In crowded visual scenes, attention is needed to selectively process information from relevant stimuli and to filter out irrelevant distracters. Accordingly, studies in humans and animals have shown that neurons in several different brain structures show enhanced responses when attention is directed into their receptive fields. However, there is still little understanding of how these ubiquitous attentional effects are actually generated through the interactions among these structures, particularly when the attentional cues arise from cognitive factors and task demands. To design an effective neural prosthesis or to treat people with attentional disorders, we need a better understanding of attention at the systems level. Three key structures thought to provide feedback to visual cortex that mediates attentional effects are the prefrontal cortex, the posterior parietal cortex and the pulvinar. In the planned experiments, we will compare the roles of each of these three structures in providing feedback to area V4 in visual cortex. Area V4 plays a central role in the relay of visual information along the ventral stream that underlies object recognition, and we have previously shown that V4 neuronal responses are modulated by attention and that damage to V4 causes attentional impairments. We have also recently shown that neurons in prefrontal cortex have attentional latencies that are short enough to mediate some of the attentional effects on V4 neuronal responses, and that prefrontal neurons have coherent activity with cells in V4. This coherent activity is time-shifted across a wide range of frequencies by about 10 ms, which may be the critical time to allow for functional interactions. In Aim 1, we will add recordings from the posterior parietal cortex to the prefrontal recordings, to compare the roles of these two structures in modulating activity in V4. The pulvinar provides an alternative anatomical route for signals from prefrontal and parietal cortex to influence V4. Therefore, in Aim 2, we will record simultaneously in the pulvinar and area V4, to test whether pulvinar neuronal properties are consistent with this feedback role. However, neurophysiological recordings alone can only provide evidence for correlations in activity, not for causality. Therefore, in Aim 3, we will supplement the neural recordings with suppression of activity in prefrontal and parietal cortex and pulvinar, to test causal hypotheses about the role of feedback from each structure in modulating V4 responses. For these experiments, we will use techniques that we and our collaborators have recently developed for the optogenetic suppression of neural activity using the proton pump, Arch-T, which is delivered by lentivirus. With Arch-T we will be able to suppress activity with resolution in the tens of milliseconds, at critical time points, to gain new mechanistic insights into the feedback to V4. In total, we expect these studies to give us the best account so far of how the interactions among multiple brain structures leads to effective visual processing with attention.       ","ACTIVITY":"R01","ADMINISTERING_IC":"EY","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"06/23/2014","BUDGET_START":"07/01/2014","BUDGET_END":"06/30/2015","CFDA_CODE":"867","CORE_PROJECT_NUM":"R01EY017292","ED_INST_TYPE":"ORGANIZED RESEARCH UNITS","FOA_NUMBER":"PA-10-067","FULL_PROJECT_NUM":"5R01EY017292-09","FUNDING_ICs":"NEI:395018\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL EYE INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"CAMBRIDGE","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"NONE","ORG_DISTRICT":"07","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"MASSACHUSETTS INSTITUTE OF TECHNOLOGY","ORG_STATE":"MA","ORG_ZIPCODE":"02142","PHR":" The aims of the project are to give us mechanistic, biological insights into how attention controls our visual processing abilities. These new insights will aid in the development of a neuro-prothesis for blindness and will also help us develop new treatments for people suffering attentional disorders.            ","PI_IDS":"8460458;","PI_NAMEs":"DESIMONE, ROBERT;","PROGRAM_OFFICER_NAME":"ARAJ, HOUMAM H","PROJECT_START":"04/01/2006","PROJECT_END":"06/30/2016","PROJECT_TERMS":"Accounting;Animals;Area;area V4;Attention;Automobile Driving;base;Biological;Blindness;Brain;Cell Communication;Cell Nucleus;Cells;Cognitive;Crowding;Cues;Data;design;Development;Disease;Electrodes;Etiology;extrastriate visual cortex;Feedback;Frequencies (time pattern);frontal eye fields;Goals;Human;Impairment;information processing;insight;Laboratories;Lateral;Maintenance;Mediating;Methods;millisecond;Monkeys;neural prosthesis;neuromechanism;Neurons;neurophysiology;neuroregulation;object recognition;optogenetics;Parietal Lobe;Phase;Play;Population;Positioning Attribute;Prefrontal Cortex;Primates;Process;Property;Proton Pump;Pulvinar structure;receptive field;relating to nervous system;research study;Resolution;response;Retina;Role;Route;selective attention;Signal Transduction;Source;Stimulus;Stream;Structure;Subfamily lentivirinae;Synapses;System;Techniques;Testing;Thalamic structure;Time;tool;Visual;Visual Cortex;visual information;visual process;visual processing;Work","PROJECT_TITLE":"Neural Mechanisms of Selective Attention","SERIAL_NUMBER":"17292","STUDY_SECTION":"COG","STUDY_SECTION_NAME":"Cognitive Neuroscience Study Section","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"9","TOTAL_COST":"395018","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8645559","ABSTRACT_TEXT":"PROJECT SUMMARY: The Biostatistics and Data Management Core (Core E) proposal here is part of a Program Project Grant (PPG) application to elucidate mechanisms of brain degeneration in hereditary and sporadic frontotemporal dementias (FTD) or frontotemporal lobar degeneration (FTLD). This core supports all data management, statistical, and computing needs, as well as maintains the PPG database for data from patient-oriented studies for all Cores and Projects 1-4 within this PPG. The  provided services includes: (a) support for data form/questionnaire design and development, database development and management, data entry, database audit trail, database security, database backup, and stringent data quality control procedures;(b) computing and programming support for all PPG activities, including implementation and integration of hardware and software upgrades necessary for data management and research, as well as routine and archival off-site backup of computing systems  central to the PPG, including the PPG database;(c) biostatistical support for all study aspects from inception to publication, including development of study design, performing sample size and power calculations, randomization schemes, and performing analyses of PPG data;and (d) development of new statistical methodologies where needed for data analysis. Thus, Core E plays an important and significant role that is critical to the progress of research and the conduct of studies in this PPG. The studies proposed in this Core taken together with the complementary studies conducted in the other Cores and all 4 Projects in this PPG will lead to a better understanding of the neurodegenerative mechanisms underiying FTLD with tau pathology and FTLD with TDP-43 pathology which is likely to enhance efforts to develop better diagnostics and therapeutic interventions for these disorders.","ACTIVITY":"P01","ADMINISTERING_IC":"AG","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"02/24/2014","BUDGET_START":"03/01/2014","BUDGET_END":"02/28/2015","CFDA_CODE":"","CORE_PROJECT_NUM":"P01AG017586","ED_INST_TYPE":"","FOA_NUMBER":"","FULL_PROJECT_NUM":"5P01AG017586-14","FUNDING_ICs":"NIA:119049\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE ON AGING","NIH_SPENDING_CATS":"","ORG_CITY":"PHILADELPHIA","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"02","ORG_DUNS":"","ORG_FIPS":"","ORG_NAME":"UNIVERSITY OF PENNSYLVANIA","ORG_STATE":"PA","ORG_ZIPCODE":"","PHR":"RELEVANCE: Working with other cores and projects. Core E will help to better understand the neurodegenerative mechanisms underiying FTLD with tau pathology and FTLD with TDP-43 pathology which is likely to enhance efforts to develop better diagnostics and therapeutic interventions for these disorders. This will help to prevent FTLD and improve the quality of life of FTLD.","PI_IDS":"8566158;","PI_NAMEs":"XIE, SHARON XIANGWEN;","PROGRAM_OFFICER_NAME":"","PROJECT_START":"","PROJECT_END":"","PROJECT_TERMS":"abstracting;Biometry;Brain;Clinical;Computer software;Computer Systems;Consult;Data;Data Analyses;data management;Data Quality;Databases;Development;Diagnostic;Disease;Frontotemporal Dementia;Frontotemporal Lobar Degenerations;Generations;Genetic;Genetic Markers;Genotype;improved;Inherited;Lead;Manuscripts;Methodology;Nerve Degeneration;neuropathology;operation;Pathology;patient oriented research;Phenotype;Play;Preparation;prevent;Procedures;Program Research Project Grants;programs;protein TDP-43;Publications;Quality Control;Quality of life;Questionnaire Designs;Randomized;relational database;Reporting;Research;Research Design;Research Personnel;Role;Sample Size;Scheme;Security;Services;Site;Statistical Computing;Statistical Methods;tau Proteins;Therapeutic Intervention;Work","PROJECT_TITLE":"BIOSTATISTIC AND DATA MANAGEMENT CORE","SERIAL_NUMBER":"17586","STUDY_SECTION":"ZAG1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"8575","SUFFIX":"","SUPPORT_YEAR":"14","TOTAL_COST":"","TOTAL_COST_SUB_PROJECT":"119049"}
{"APPLICATION_ID":"8660058","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): Developing a Diabetes Numeracy Intervention for American Indians/Alaska Natives Project Summary Patients with diabetes must engage in a variety of self-care behaviors, including appropriate dietary practices, blood glucose self-monitoring, and medication management. Important to each of these behaviors is the capacity to understand and use numbers (e.g., counting carbohydrates). Referred to as \"numeracy,\" such abilities are associated with a variety of diabetes self-care behaviors and outcomes (e.g., glycemic control).  Although the prevalence of diabetes has raised nationwide, American Indians and Alaska Natives (AI/ANs) are diagnosed with diabetes at 2-3 times the rate of non-Hispanic Whites. And, yet, Native people are at risk for limitations in the numerical skills that are criticl for diabetes management. Although deficits in numeracy are widespread, such limitations are particularly common among racial/ethnic minorities and individuals with limited income and education. As a result of restricted educational opportunities and high rates of poverty in many AI/AN communities, Native people with diabetes are at risk for limitations in diabetes-related numeracy.  Despite evidence of a link between numeracy and health, no interventions aimed at improving health- related numeracy have been published. The goal of the proposed project is to develop and pilot test an intervention to improve diabetes-related numerical skills among AI/ANs with diabetes. The aims of the project are the following: (1) To develop a culturally appropriate intervention to teach the numerical skills required for successful diabetes self-management;(2) To assess change in numeracy skills following intervention;and (3) To explore change in diabetes self-efficacy, self-care behavior, and clinical outcomes following intervention and to assess whether change in numeracy predicts change in these secondary outcomes.  The INTervention to Enhance Numeracy in Diabetes (INTEND) will be adapted from two existing numeracy curricula - Extending Mathematical Power (EMPower) and Statistics for Action (SfA) - which were developed to teach adults the math skills needed to manage everyday numerical tasks. The project team, which includes experts in AI/AN health and diabetes numeracy as well as the developers of EMPower and SfA, will adapt these curricula to address diabetes management among AI/ANs. The INTEND will be tested in a randomized controlled trial involving 130 AI/AN patients with diabetes from Yakama Indian Health Center in Toppenish, WA. Analyses will assess whether patients who participate in the INTEND show significantly greater improvement in numeracy, self-efficacy, self-care behavior, and clinical outcomes than do control patients.  As no interventions designed to improve health-related numeracy have been reported in the literature, this innovative project will advance science related to numeracy and highlight a new avenue for intervening with AI/ANs and other populations at risk for diabetes and its complications. As similar numerical skills are required in the management of other serious health problems, such as cardiovascular disease and hypertension, the results of this work may inform the development of effective interventions for other conditions as well.        ","ACTIVITY":"R21","ADMINISTERING_IC":"DK","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"04/15/2014","BUDGET_START":"05/01/2014","BUDGET_END":"04/30/2015","CFDA_CODE":"847","CORE_PROJECT_NUM":"R21DK093946","ED_INST_TYPE":"SCHOOLS OF PUBLIC HEALTH","FOA_NUMBER":"PA-12-157","FULL_PROJECT_NUM":"5R21DK093946-02","FUNDING_ICs":"NIDDK:232044\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES","NIH_SPENDING_CATS":"","ORG_CITY":"AURORA","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"PUBLIC HEALTH &PREV MEDICINE","ORG_DISTRICT":"06","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF COLORADO DENVER","ORG_STATE":"CO","ORG_ZIPCODE":"800452570","PHR":"PUBLIC HEALTH RELEVANCE: Numeracy - defined as the ability to understand and use numbers - is associated with health outcomes among people with diabetes. The purpose of this project is to develop and conduct initial testing of an intervention designed to teach the numerical skills patients need to manage their diabetes (e.g., counting carbohydrates, understanding blood glucose values). The results of this work will help us to understand whether it is possible to improve health-related numerical skills and whether diabetes outcomes can be improved as a result.            ","PI_IDS":"7924816;","PI_NAMEs":"BREGA, ANGELA GWEN;","PROGRAM_OFFICER_NAME":"HUNTER, CHRISTINE ","PROJECT_START":"05/10/2013","PROJECT_END":"04/30/2015","PROJECT_TERMS":"Address;Adult;Affect;Age;American Indian and Alaska Native;base;Behavior;Blood Glucose;Blood Glucose Self-Monitoring;Carbohydrates;Cardiovascular Diseases;Clinical;Clinical Research;Colorado;Communities;Comprehension;design;Development;diabetes management;Diabetes Mellitus;Diagnosis;Dietary Practices;Disease;Doctor of Philosophy;Dose;Educational aspects;Educational Curriculum;Educational process of instructing;effective intervention;Endocrine System Diseases;experience;follow-up;Food Labeling;Foundations;glycemic control;Goals;Health;Health care facility;health literacy;Hypertension;improved;Income;Individual;innovation;insight;Insulin;Intervention;Knowledge;Link;Literature;mathematical ability;Mathematics;Medication Management;Metabolic Diseases;Minority Groups;National Institute of Diabetes and Digestive and Kidney Diseases;Native-Born;Not Hispanic or Latino;Outcome;Participant;Patients;Pharmaceutical Preparations;Population;Populations at Risk;Poverty;Prevalence;public health relevance;Publishing;Randomized Controlled Trials;Reading;Recruitment Activity;Reporting;Research;Research Personnel;Research Project Grants;Resources;Risk;Sampling;Science;secondary outcome;Self Care;Self Efficacy;Self Management;skills;statistics;Testing;therapy design;Time;Training;Universities;Visit;Work","PROJECT_TITLE":"Developing a Diabetes Numeracy Intervention for American Indians/Alaska Natives","SERIAL_NUMBER":"93946","STUDY_SECTION":"ZRG1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"2","TOTAL_COST":"232044","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8690788","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): The focus of this proposal is to develop further potential glycomarkers we have identified for pancreatic cancer and breast cancer, as well as to discover new glycomarkers by detailed glycomic analysis of the tumor initiating cells (TIC) of pancreatic and breast cancer and of tumor-associated \"stellate\" cells that surround pancreatic cancer. Clearly, developing biomarkers for pancreatic and breast cancer is of critical importance in the early detection of cancers. During the first cycle of the NCI U01 focused on Glycans and Cancer, we analyzed pancreatic ductal fluid from those with pancreatic ductal adenocarcinoma and controls using glycomic analysis tools developed in our NCRR Resource for Biomedical Glycomics. We have identified several potential glycomarkers that will be developed in this competitive renewal application. Most notably, we have identified a unique N-glycan that shows promise as a sensitive and specific marker of pancreatic adenocarcinoma. In addition, we developed a Targeted Glycoproteomics technology and used it to identify potential markers in invasive ductal breast carcinoma tissue. Two glycoprotein glycomarkers were identified and verified in serum samples. A newly devised sandwich ELISA to detect the specific glycoform of one of these markers shows promise in distinguishing serum from patients with breast cancer and those with benign polycystic disease. In the discovery Aim of this proposal, we will prepare TIC from pancreatic adenocarcinoma by cell sorting and apply glycomics technologies to identify differences between TIC and differentiated tumor cells. A similar strategy will be utilize using cultured breast cancer cell lines. As we have during the first cycle of the U01, we will exploit these differences by devising serum assays to identify potential glycoprotein glycoform markers. Similarly, we will analyze tumor-associated fibroblastic \"stellate\" cells from pancreatic cancers and grown in culture for potential glycomarkers. These cells surround these cancers and may, therefore, secrete or release potential glycomarkers for the cancer that can be detected in serum.            ","ACTIVITY":"U01","ADMINISTERING_IC":"CA","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"07/30/2014","BUDGET_START":"07/01/2014","BUDGET_END":"06/30/2015","CFDA_CODE":"394","CORE_PROJECT_NUM":"U01CA128454","ED_INST_TYPE":"ORGANIZED RESEARCH UNITS","FOA_NUMBER":"RFA-CA-11-009","FULL_PROJECT_NUM":"5U01CA128454-08","FUNDING_ICs":"NCI:441980\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL CANCER INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"ATHENS","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"NONE","ORG_DISTRICT":"10","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF GEORGIA","ORG_STATE":"GA","ORG_ZIPCODE":"306025016","PHR":" The studies in this proposal will both develop potential glycan biomarkers for pancreatic and breast cancer that we have developed over the first time-frame of the U01, as well as discover new glycomarkers for two specific types of cells in these tumors. These cells are either thought to function in the initiation of tumors, called tumor-initiating cels, or surround them, called tumor-associated stellate cells. Validation of any of the potential glycomarkers originating in our work could have a significant impact on the early diagnosis of cancer.                ","PI_IDS":"1883968;","PI_NAMEs":"PIERCE, J. MICHAEL;","PROGRAM_OFFICER_NAME":"KRUEGER, KARL E","PROJECT_START":"07/25/2007","PROJECT_END":"06/30/2017","PROJECT_TERMS":"Adenocarcinoma Cell;Antibodies;base;Benign;Biological;Biological Assay;Biological Markers;biomedical resource;Breast Cancer Cell;Cancer cell line;Cell Culture Techniques;Cell Line;Cell Separation;cell type;Cells;Chinese Hamster Ovary Cell;Collaborations;Collection;Cultured Cells;Cyst;Detection;Development;Disease;Ductal;ductal breast carcinoma;Early Detection Research Network;Early Diagnosis;Enzyme-Linked Immunosorbent Assay;Epitopes;Funding;Genes;Gland;Glycoproteins;Grant;Human;ID2 gene;innovative technologies;Lead;Lectin;Liquid substance;malignant breast neoplasm;Malignant neoplasm of pancreas;Malignant Neoplasms;Mammary Neoplasms;Methods;Mus;Myofibroblast;National Center for Research Resources;neoplastic cell;NOD/SCID mouse;novel;Pancreas;Pancreatic Adenocarcinoma;pancreatic cancer cells;Pancreatic Ductal Adenocarcinoma;pancreatic neoplasm;Pancreatitis;Patients;periostin;Phase;polypeptide;Polysaccharides;Polysialic Acid;Primary Neoplasm;Proliferating;Proteins;Proteomics;Sampling;Screening for cancer;Sensitivity and Specificity;Serum;Sorting - Cell Movement;Staging;stellate cell;Technology;Testing;Time;Tissue Microarray;Tissues;tool;Transcript;tumor;tumor initiation;Tumor Markers;tumor progression;tumor xenograft;Validation;Work;Xenograft Model;Xenograft procedure","PROJECT_TITLE":"Discovery and Development of Cancer Glycomarkers","SERIAL_NUMBER":"128454","STUDY_SECTION":"ZCA1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"8","TOTAL_COST":"441980","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8939807","ABSTRACT_TEXT":"Previously we have studies the contribution of histone modifications, DNA methylation and their regulatory enzymes to transcriptional regulation in a variety of cellular systems. Our latest efforts have focused on how histone variants contribute to the regulation of chromatin structure and transcription.    Nucleosomes are present throughout the genome and must be dynamically regulated to accommodate binding of transcription factors and RNA polymerase machineries by various mechanisms. Despite the development of protocols and techniques that have enabled us to map nucleosome occupancy genome-wide, the dynamic properties of nucleosomes remain poorly understood, particularly in mammalian cells. The histone variant H3.3 is incorporated into chromatin independently of DNA replication and requires displacement of existing nucleosomes for its deposition. However, it is not clear how deposition of the histone variant is regulated. We developed a system to study the DNA replication-independent turnover of nucleosomes containing the histone variant H3.3 in mammalian cells. By measuring the genome-wide incorporation of H3.3 at different time points following epitope-tagged H3.3 expression, we find three categories of H3.3-nucleosome turnover in vivo: rapid turnover, intermediate turnover and, specifically at telomeres, slow turnover. Our data indicate that H3.3-containing nucleosomes at enhancers and promoters undergo rapid turnover that is associated with active histone modification marks including H3K4me1, H3K4me3, H3K9ac, H3K27ac and the histone variant H2A.Z. The rate of turnover is negatively correlated with H3K27me3 at regulatory regions and with H3K36me3 at gene bodies.  In addition, we have worked with our collaborators using model systems including Drosophila flies and chicken to investigate the contribution of chromatin and epigenetic mechanisms to cellular memory and differentiation.","ACTIVITY":"ZIA","ADMINISTERING_IC":"HL","APPLICATION_TYPE":"1","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"","BUDGET_START":"","BUDGET_END":"","CFDA_CODE":"","CORE_PROJECT_NUM":"ZIAHL005801","ED_INST_TYPE":"","FOA_NUMBER":"","FULL_PROJECT_NUM":"1ZIAHL005801-12","FUNDING_ICs":"NHLBI:1238819\\","FUNDING_MECHANISM":"Intramural Research","FY":"2014","IC_NAME":"NATIONAL HEART, LUNG, AND BLOOD INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"","ORG_COUNTRY":"","ORG_DEPT":"","ORG_DISTRICT":"","ORG_DUNS":"","ORG_FIPS":"","ORG_NAME":"HEART, LUNG, AND BLOOD INSTITUTE","ORG_STATE":"","ORG_ZIPCODE":"","PHR":"","PI_IDS":"9694360;","PI_NAMEs":"ZHAO, KEJI;","PROGRAM_OFFICER_NAME":"","PROJECT_START":"","PROJECT_END":"","PROJECT_TERMS":"Binding (Molecular Function);Biological Models;Categories;Chickens;Chip seq;Chromatin;Chromatin Structure;Data;Deoxyribonucleases;Deposition;Development;Disease;DNA biosynthesis;DNA Methylation;DNA-Directed RNA Polymerase;Drosophila genus;Enhancers;Enzymes;Epigenetic Process;epigenome;Epitopes;fly;Genes;Genetic Transcription;Genome;genome-wide;Goals;histone modification;Histones;in vivo;interest;Mammalian Cell;Maps;Measures;Memory;Nucleic Acid Regulatory Sequences;Nucleosomes;Promotor (Genetics);Property;protocol development;Regulation;System;Techniques;telomere;Time;transcription factor;Transcriptional Regulation;transcriptome sequencing;Variant;Work","PROJECT_TITLE":"Genome-wide mapping of histone modifications","SERIAL_NUMBER":"5801","STUDY_SECTION":"","STUDY_SECTION_NAME":"","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"12","TOTAL_COST":"1238819","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8694239","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant):  The prognosis for pancreatic cancer (PC) patients is dismal, with a 5-year survival rate of less than 6%. This is in part due to the propensity of PC to metastasize prior to disease detection and the resistance of these metastatic tumors to cytotoxic therapies. A significant portion of therapeutic resistance in pancreatic cancers comes from the support of a unique tumor microenvironment. This tumor microenvironment includes significant numbers of infiltrating myeloid cells including tumor-associated macrophages, which exacerbate responses to therapy by inducing immunosuppression and increasing the presence of cancer stem cells. Thus, where clinically feasible reprogramming the immune microenvironment would improve responses to cytotoxic therapy even in resistant tumors. One unique approach to this problem is to target the colony-stimulating factor 1 receptor (CSF1R). Previous studies have shown that genetic loss of colony stimulating factor-1, a critical cytokine for the recruitment, survival, and activation of macrophages, can decease the progression of mammary and neuroendocrine pancreatic tumors. Our own work has shown that inhibiting CSF1R can vastly improve responses to chemotherapy and decrease metastatic spread in pancreatic tumor models. We have now extended these observations and demonstrated that CSF1R inhibition 1) rapidly reprograms tumor-infiltrating macrophage responses, 2) decreases the frequency of tumor initiating cells, and 3) leads to recovery of anti-tumor cytotoxic responses by neutrophils and T lymphocytes. In so doing, CSF1R inhibition reprograms the tumor microenvironment to increase responses to chemotherapy and decrease metastatic spread. Thus, our hypothesis is that blockade of CSF1R signaling reprograms the tumor microenvironment to improve responses to chemo- and immunotherapy. The long-term goals of the proposed studies are to initiate new clinical trials testing this approach in metastatic PC. However, in order to inform these trials and test our overall hypothesis the following specific aims are critical. Aim 1: Determine the mechanisms by which macrophages regulate metastatic relapse. Aim 2: Determine the functional role of CSF1R blockade in granulocyte reprogramming. Aim 3: Determine the optimum therapeutic regimen for targeting CSF1R to improve immunotherapy. These Aims form the basis of our proposed studies, which will use a combination of clinically translatable agents and genetic mouse models to: 1) fundamentally understand the biological underpinnings by which myeloid cells regulate chemotherapeutic response. And 2) to identify and validate targets to exploit these biological processes for therapeutic benefit. Thus, this application will develop targeted inhibition of CSF1R as a novel immunotherapeutic agent to improve outcomes for pancreatic cancer patients.          ","ACTIVITY":"R01","ADMINISTERING_IC":"CA","APPLICATION_TYPE":"1","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"03/26/2014","BUDGET_START":"04/01/2014","BUDGET_END":"02/28/2015","CFDA_CODE":"395","CORE_PROJECT_NUM":"R01CA177670","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"PA-11-260","FULL_PROJECT_NUM":"1R01CA177670-01A1","FUNDING_ICs":"NCI:316178\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL CANCER INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"SAINT LOUIS","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"INTERNAL MEDICINE/MEDICINE","ORG_DISTRICT":"01","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"WASHINGTON UNIVERSITY","ORG_STATE":"MO","ORG_ZIPCODE":"631304862","PHR":"PUBLIC HEALTH RELEVANCE:  The response of pancreatic cancer patients to current cytotoxic therapies is dismal;this is in part due the support of a unique immune microenvironment which blocks effective therapy. Therefore, the reprogramming immune responses to facilitate anti-tumor immunity would be effective at extending survival in pancreatic cancer patients. We have identified colony-stimulating factor 1 receptor (CSF1R) signaling as a significant regulator of immune-mediated chemoprotection and in order to develop this approach for clinical application, these studies will test the ability of CSF1R-inhibition to improve responses to chemo- and immunotherapy in metastatic pancreatic cancer.              ","PI_IDS":"8710339;","PI_NAMEs":"DENARDO, DAVID G;","PROGRAM_OFFICER_NAME":"MUSZYNSKI, KAREN ","PROJECT_START":"04/01/2014","PROJECT_END":"02/28/2019","PROJECT_TERMS":"Acute;Address;Adenocarcinoma Cell;Adjuvant;Antigen Presentation;Antitumor Response;base;Biological;Biological Process;Biological Response Modifiers;cancer cell;Cancer Patient;Cancer stem cell;CD8B1 gene;Cells;Chemoprotection;Chemosensitization;chemotherapy;Clinical;clinical application;Clinical Trials;CSF1 gene;CXCL10 gene;CXCL11 gene;cytokine;cytotoxic;Cytotoxic agent;Cytotoxic Chemotherapy;Cytotoxic T-Lymphocytes;Dendritic Cells;design;Detection;Development;Diagnosis;Disease;effective therapy;Frequencies (time pattern);Genetic;Goals;granulocyte;Granulocyte Precursor Cells;Growth;Immature Granulocyte;Immature Monocyte;Immune;Immune response;Immunity;Immunosuppressive Agents;Immunotherapeutic agent;Immunotherapy;improved;Infiltration;insight;Islet Cell Tumor;Leukocytes;macrophage;Macrophage Activation;Macrophage Colony-Stimulating Factor;Macrophage Colony-Stimulating Factor Receptor;Malignant neoplasm of pancreas;Malignant Neoplasms;Mammary gland;Mammary Neoplasms;Mediating;Mediator of activation protein;Medical;Modeling;mouse model;Mus;Myelogenous;Myeloid Cells;Natural immunosuppression;Natural Killer Cells;Neoplasm Metastasis;Neuroendocrine Tumors;neutrophil;novel;Outcome;outcome forecast;palliative;Pancreas;Pancreatic Ductal Adenocarcinoma;pancreatic neoplasm;Patients;Phase;Primary Neoplasm;Property;public health relevance;Publishing;Reagent;Receptor Inhibition;Receptor Signaling;Recovery;Regimen;Relapse;Research;Resistance;response;Role;Signal Pathway;stem;Survival Rate;T-Lymphocyte;Testing;Therapeutic;therapy development;tumor;Tumor Immunity;tumor microenvironment;tumor progression;unpublished works;Work","PROJECT_TITLE":"REPROGRAMMING THE METASTATIC MICROENVIRONMENT OF PANCREATIC CANCER THROUGH CSF1R","SERIAL_NUMBER":"177670","STUDY_SECTION":"CII","STUDY_SECTION_NAME":"Cancer Immunopathology and Immunotherapy Study Section","SUBPROJECT_ID":"","SUFFIX":"A1","SUPPORT_YEAR":"1","TOTAL_COST":"316178","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8627970","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): Living cells gain energy for growth and survival by transferring electrons between the products of catabolism and a suitable electron acceptor. The most favorable terminal electron acceptor is oxygen, but in oxygen-poor environments most cells use other soluble factors to accept the electrons generated by metabolism. Bacteria in the genus Shewanella can actually use solid extracellular metals as substrates for respiration, and they have evolved a series of periplasmic and outer-membrane proteins to serve as a direct electrical junction with these metals. Several members of the shewanellae have clinical relevance as opportunistic pathogens, and the basis of their unique respiratory abilities thus warrants further investigation. Furthermore, the existence of a genetically-encoded pathway between manufactured circuits and the central metabolism of living cells opens new vistas in studying and engineering microorganisms. Recent results suggest that these conduits can also pass current in reverse, allowing extracellular electrons to enter the cell and drive synthetic processes. If combined with carbon fixation, applied current could make a versatile input for the production of high-value chemicals, including pharmaceuticals. This proposal outlines research to characterize and improve the capacity of Shewanella cells to accept electrical current, using electrically active bioreactors in combination with microscopy of cells expressing fluorescent protein sensors, transcriptome sequencing, and reverse genetics assays. Finally, a strain of E. coli expressing genes from Shewanella will be constructed in order to define an efficient genetic circuit conferring electron uptake.        ","ACTIVITY":"F32","ADMINISTERING_IC":"GM","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"07/23/2014","BUDGET_START":"08/01/2014","BUDGET_END":"07/31/2015","CFDA_CODE":"859","CORE_PROJECT_NUM":"F32GM105122","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"PA-11-113","FULL_PROJECT_NUM":"5F32GM105122-02","FUNDING_ICs":"NIGMS:53282\\","FUNDING_MECHANISM":"Training, Individual","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES","NIH_SPENDING_CATS":"","ORG_CITY":"BOSTON","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"BIOLOGY","ORG_DISTRICT":"07","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"HARVARD MEDICAL SCHOOL","ORG_STATE":"MA","ORG_ZIPCODE":"02115","PHR":"PUBLIC HEALTH RELEVANCE: The studies proposed in this document will contribute to our knowledge of microbial energetics of an opportunistic pathogen, and establish a chassis for efficient production of important biomedical products in the future.            ","PI_IDS":"11325355;","PI_NAMEs":"MACKELLAR, DREW CARL;","PROGRAM_OFFICER_NAME":"FLICKER, PAULA F.","PROJECT_START":"08/01/2013","PROJECT_END":"07/31/2015","PROJECT_TERMS":"Address;Affect;Anodes;ATP Synthesis Pathway;Bacteria;base;Biological Assay;biological systems;Biology;Bioreactors;Bioremediations;carbon fixation;Catabolism;Cathodes;Cell membrane;Cell physiology;Cells;cellular engineering;Chemicals;Chimeric Proteins;clinically relevant;Communication;Couples;Cytochromes;Cytoplasm;Data;driving force;electrical potential;Electron Transport;Electrons;Energy-Generating Resources;Engineering;Environment;Equilibrium;Escherichia coli;extracellular;Fermentation;Future;Gene Expression;Genes;Genetic;Geobacter;Growth;Heating;improved;Investigation;Life;Light;Measures;member;Membrane;Membrane Proteins;metabolic engineering;Metabolism;Metals;Microbe;microbial;Microbial Biofilms;microorganism;Microscopy;Modeling;Monitor;mutant;NADH;Nature;Organism;Oxidants;Oxidation-Reduction;Oxygen;pathogen;Pathway interactions;periplasm;Pharmacologic Substance;Photosynthesis;positional cloning;Potential Energy;Process;Production;Proteins;public health relevance;Reaction;reconstitution;Relative (related person);Research;Respiration;respiratory;sensor;Series;Shewanella;Solid;Stimulus;System;Testing;Transcript;transcriptome sequencing;uptake","PROJECT_TITLE":"Direct Stimulation of Bacterial Metabolism with Applied Electrical Current","SERIAL_NUMBER":"105122","STUDY_SECTION":"ZRG1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"2","TOTAL_COST":"53282","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8733718","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): This proposal builds upon the accomplishments made during the previous funding period and requests continuing support of the Center of Biomedical Research Excellence (COBRE) on Obesity and Cardiovascular Diseases (COCVD). Kentucky ranks within the top 10 states for the prevalence of obesity and cardiovascular diseases, and the epidemic is not abating. Thus, it is imperative that mechanisms linking obesity to cardiovascular diseases are identified. During the 4 years of support the COCVD has made significant strides advancing knowledge on obesity-associated cardiovascular diseases through support of junior investigators and the development of research cores. As a result, we have experienced outstanding success, with graduation of 75% of 12 supported junior investigators to independent R01 support, including 15 new NIH R01s. The program has graduated 2 junior faculty/year to NIH R01 level support, with 125 publications from junior investigators, and an additional 318 publications from mentors. In addition, we have supported 7 pilot projects that have contributed to 58 publications. New research cores to quantify obesity phenotypes and to provide analytical services in lipidomics have markedly increased the research infrastructure. As a direct result of COCVD activities, the institution competed successfully for a CTSA to establish the Center for Clinical and Translational Sciences. In the second phase of the COCVD we propose to create a nationally recognized Center of Research Excellence to define mechanisms linking the epidemic of obesity to cardiovascular diseases, the primary cause of death in the obese population. To accomplish this goal, we will (1) develop a critical mass of funded investigators including basic and physician scientists with research programs directly related to the Center's unifying theme, (2) provide strong mentoring programs, (2) recruit new investigators to the Center through pilot project grant support, which will be leveraged by the institution and the CTSA, (4) expand and further develop an Analytical Core (with a focus on lipidomics), a Physiologic Core to quantify obesity and cardiovascular phenotypes, and a Pathology Core to assess tissue histology.        ","ACTIVITY":"P20","ADMINISTERING_IC":"GM","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"08/12/2014","BUDGET_START":"08/01/2014","BUDGET_END":"07/31/2015","CFDA_CODE":"859","CORE_PROJECT_NUM":"P20GM103527","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"PAR-12-224","FULL_PROJECT_NUM":"5P20GM103527-07","FUNDING_ICs":"NIGMS:2250588\\","FUNDING_MECHANISM":"Research Centers","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES","NIH_SPENDING_CATS":"","ORG_CITY":"LEXINGTON","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"PHARMACOLOGY","ORG_DISTRICT":"06","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF KENTUCKY","ORG_STATE":"KY","ORG_ZIPCODE":"405060057","PHR":"PUBLIC HEALTH RELEVANCE: The Center of Biomedical Research Excellence on Obesity and Cardiovascular Diseases seeks to define mechanisms for the rampant prevalence of cardiovascular diseases in the obese population. We will enhance the competitiveness of junior faculty with research programs in this highly significant area through research support, mentoring, and through development and access to cutting-edge research cores.                ","PI_IDS":"1857999;","PI_NAMEs":"CASSIS, LISA A;","PROGRAM_OFFICER_NAME":"LIU, YANPING ","PROJECT_START":"09/08/2008","PROJECT_END":"07/31/2018","PROJECT_TERMS":"Abate;Adipose tissue;Area;bench to bedside;Cardiovascular Diseases;Cardiovascular system;Cause of Death;Centers of Research Excellence;Clinical Sciences;clinically significant;Core Facility;Development;Epidemic;Exhibits;experience;Faculty;Funding;Goals;Grant;Histology;Inflammation;Institution;Kentucky;Knowledge;Link;Mentors;multidisciplinary;Obesity;Obesity associated cardiovascular disease;Pathology;Phase;Phenotype;Physicians;Physiological;Pilot Projects;Positioning Attribute;Prevalence;programs;public health relevance;Publications;Recruitment Activity;Research;research and development;Research Infrastructure;Research Personnel;Research Support;Scientist;Services;success;Testing;Tissues;Translational Research;United States National Institutes of Health","PROJECT_TITLE":"Center of Research on Obesity and Cardiovascular Diseases","SERIAL_NUMBER":"103527","STUDY_SECTION":"ZGM1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"7","TOTAL_COST":"2250588","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8726764","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): Currently, caregiver intervention is the sole method of mitigating seizure-related adverse events, and there are few options for indirect monitoring on a daily basis. Approaches for non-clinical settings have included nocturnal bed sensors and accelerometry-based sensors, but these have suffered from low sensitivity (e.g., only detects nocturnal or tonic-clonic seizures) and high false-alarm rates. Investigators at RTI International and Children's National Medical Center (CNMC) propose a joint effort to develop a novel seizure alert system for daily monitoring and caregiver alert. This system will target the well-documented physiological effects due to elevated activity of the autonomic nervous system (ANS) during seizures that can be measured with unobtrusive, comfortable sensors. A multi-sensor approach will be used to increase sensitivity and precision for the detection of all generalized seizures and some types of partial seizures, excluding absence and simple partial. The overall performance objective is to demonstrate that significant seizures can be identified 95% of the time with a false event rate of less than 10%. Preliminary data collected from 16 subjects suggest that successful detection of seizures with a multi-sensor approach is highly probable. By decreasing response time and eliminating the need for constant observation, this system could have a substantial and measurable impact on the epilepsy community by decreasing the number of seizure-related injuries and deaths, improving quality of life, increasing independence for both patients and caregivers, and reducing the cost of treatment. The research plan discusses three specific aims. Aim 1: Develop and validate seizure detection algorithm with clinical data. It is hypothesized that significant seizures can be detected with hig sensitivity and precision using multiple physiological indicators of ANS escalation, including changes in heart rate and variability, respiration, skeletal muscle activity, and sweating. An automated detection algorithm will be developed and validated that uses a multi-sensor data fusion and pattern recognition approach to classify seizure and non-seizure states. Aim 2: Develop integrated prototype seizure alert device. A fully integrated prototype system will be developed, including a compact, wearable monitoring device and a remote caregiver alert unit based on robust methodology using quantitative clinical results, feedback from potential end users, and state-of-the-art technological advancements. Aim 3: Validate prototype in clinical and residential settings. The prototype seizure alert system will be tested for performance and overall usability during a clinical study at CNMC. Forty-five patient-caregiver pairs will use the system in clinical testing to assess detection performance, followed by at-home testing to assess device effectiveness, practicality, and comfort for daily use in a realistic environment.        ","ACTIVITY":"R01","ADMINISTERING_IC":"EB","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"09/05/2014","BUDGET_START":"09/01/2014","BUDGET_END":"08/31/2015","CFDA_CODE":"286","CORE_PROJECT_NUM":"R01EB014742","ED_INST_TYPE":"","FOA_NUMBER":"PAR-11-020","FULL_PROJECT_NUM":"5R01EB014742-02","FUNDING_ICs":"NIBIB:548501\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING","NIH_SPENDING_CATS":"","ORG_CITY":"RESEARCH TRIANGLE","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"04","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"RESEARCH TRIANGLE INSTITUTE","ORG_STATE":"NC","ORG_ZIPCODE":"277090155","PHR":"PUBLIC HEALTH RELEVANCE: The ultimate goal of this research is the development of a seizure alert system that can be used daily by people with epilepsy to detect the onset of generalized seizures and wirelessly alert a caregiver to provide appropriate medical intervention. The proposed research will design and develop a prototype seizure alert system that detects seizure onset via a wearable monitor containing an array of noninvasive physiological sensors and an embedded real-time detection algorithm. The developing system, which will be evaluated throughout the program in a clinical study with patients undergoing video electroencephalographic evaluation, could have a groundbreaking impact on the potential prevention of seizure-related injury and death, improve quality of life, and increase independence for patients and caregivers.","PI_IDS":"9182267 (contact);6302805;","PI_NAMEs":"GILCHRIST, KRISTIN HEDGEPATH (contact);KRONER, BARBARA L;","PROGRAM_OFFICER_NAME":"LASH, TIFFANI BAILEY","PROJECT_START":"09/01/2013","PROJECT_END":"08/31/2016","PROJECT_TERMS":"Adverse event;Algorithms;Autonomic nervous system;base;Beds;Biosensor;bone;Cardiac;Caregivers;Cellular Phone;Cessation of life;Child;Clinical;Clinical Data;Clinical Research;Communities;Computer software;Craniocerebral Trauma;cranium;Custom;Data;design;Detection;Development;Devices;Effectiveness;Electrodes;Electroencephalography;Environment;Epilepsy;Evaluation;Event;Feedback;Focal Seizure;Funding;Generalized seizures;Goals;Health;Health Personnel;heart rate variability;Home environment;improved;Incidence;Injury;International;Intervention;Interview;Joints;Laceration;Measurable;Measures;Medical;Medical Assistance;Medical center;Methodology;Methods;Monitor;monitoring device;Neurologist;novel;Outcome;Patients;Pattern;Pattern Recognition;Performance;performance tests;Personal Satisfaction;Pharmaceutical Preparations;Physiological;prevent;Prevention;programs;prototype;Psychological Stress;public health relevance;Quality of life;Reaction Time;Research;research clinical testing;Research Personnel;Respiration;Seizures;sensor;Skeletal muscle structure;Surveys;Sweat;Sweating;Symptoms;System;Testing;Time;Tonic - clonic seizures;Treatment Cost;United States;usability","PROJECT_TITLE":"Developing a mobile seizure alert device using non-invasive physiological measure","SERIAL_NUMBER":"14742","STUDY_SECTION":"ZRG1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"2","TOTAL_COST":"548501","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8689138","ABSTRACT_TEXT":"   DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the number one killer and a major cause of disability in the United States. Emerging data suggest that overproduction of reactive oxygen species (ROS) plays a causal role in the pathogenesis of atherosclerosis and other CVD. Reactive nitrogen intermediates such as peroxynitrite (ONOO-) and nitrogen-dioxide radicals, formed by rapid reaction between nitric oxide (.NO) and ROS, react with carbohydrates, DNA bases, protein tyrosine/tryptophan, and unsaturated fatty acids to form relatively stable nitrated products. In the past eight years, our research team has revealed that a novel class of nitrated unsaturated fatty acids (NO2-FA) is generated by NO- mediated oxidative reactions and exerts pleiotropic cell signaling actions with a property of anti-oxidative stress. Recently, we have well documented that NO2- FA exerted anti-proliferative and pro-apoptotic effects in vascular smooth muscle cells (VSMC) via activation of Nrf2 with an increase in Nrf2 stability in vitro. Furthermore, we have demonstrated that NO2-FA inhibited vascular lesion formation after arterial injury. These key results let us to test our central hypothesis that NO2-FA-operated Nrf2 signaling play a critical role in protecting vasculature from vascular lesion formation, thereby contributing to maintenance of vascular homeostasis. As Nrf2 signaling is critical for the anti-oxidative defense in various organs including the cardiovascular system, understanding of the endogenous NO2-FA-operated Nrf2 signaling will provide novel insights into redox homeostasis and the development of new therapeutic strategies for the treatment of CVD. Specifically, we will 1) Define NO2-FA-operated Nrf2 signaling in the control of VSMC fate in vitro;2) Define the mechanisms of NO2-FA- mediated Nrf2 activation in VSMC;3) Determine the NO2-FA-operated Nrf2 signaling as a \"vasculo-protective\" determinant in vascular lesion formation in vivo.      ","ACTIVITY":"R01","ADMINISTERING_IC":"HL","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"06/20/2014","BUDGET_START":"07/01/2014","BUDGET_END":"06/30/2015","CFDA_CODE":"837","CORE_PROJECT_NUM":"R01HL105114","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"PA-07-070","FULL_PROJECT_NUM":"5R01HL105114-05","FUNDING_ICs":"NHLBI:515414\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL HEART, LUNG, AND BLOOD INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"ANN ARBOR","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"INTERNAL MEDICINE/MEDICINE","ORG_DISTRICT":"12","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF MICHIGAN","ORG_STATE":"MI","ORG_ZIPCODE":"481091274","PHR":" Cardiovascular disease (CVD) is the number one killer and a major cause of disability in the United States. Overproduction of reactive oxygen species (ROS) plays a causal role in the pathogenesis of CVD;however, nonselective approach of scavenging all ROS appears to have deleterious effects. This proposal will address the vasculo-protective effect of nitro-fatty acids (NO2-FA), which is mediated by activation of Nrf2 signaling, an anti-oxidative system. The outcome of these studies will provide novel perspectives for the rational design and development of NO2-FA derivatives with unique properties of enhancing of anti-oxidative defense rather than simply blockade of ROS production for CVD treatment.         ","PI_IDS":"6099117;","PI_NAMEs":"CHEN, YUQING EUGENE;","PROGRAM_OFFICER_NAME":"GAO, YUNLING ","PROJECT_START":"07/01/2010","PROJECT_END":"06/30/2015","PROJECT_TERMS":"Address;Antioxidants;Apoptosis;Apoptotic;Arterial Fatty Streak;Arterial Injury;Arteries;Atherosclerosis;Attenuated;base;Binding (Molecular Function);Biological Models;Blood Circulation;Blood Vessels;Carbohydrates;Cardiovascular Diseases;Cardiovascular Physiology;Cardiovascular system;cell growth;clinical effect;Clinical Trials;Cysteine;Data;design;Development;disability;DNA;Dominant-Negative Mutation;Exhibits;Failure (biologic function);Fatty Acids;femoral artery;Free Radical Scavenging;Growth;Heme Oxygenase (Decyclizing);Homeostasis;Human;human MYH11 protein;In Vitro;in vivo;Inhibition of Apoptosis;inhibitor/antagonist;injured;Injury;insight;Investigation;Knock-out;Knockout Mice;Lesion;loss of function;Maintenance;Mediating;Modification;Molecular;Mus;mutant;Mutant Strains Mice;Names;Nitrates;Nitric Oxide;nitroalkene;Nitrogen;nitrogen dioxide radical;novel;novel therapeutics;Organ;Outcome;Outcome Study;overexpression;Oxidation-Reduction;Oxidative Stress;Pathogenesis;Pathway interactions;Peroxonitrite;Pharmaceutical Preparations;Physiological;Play;Probucol;Production;Property;protective effect;Proteins;Reaction;Reactive Oxygen Species;Regulation;Research;response;response to injury;Role;Signal Transduction;Small Interfering RNA;Smooth Muscle Myocytes;Supplementation;System;Testing;tool;Transgenic Mice;treatment strategy;Tryptophan;Tyrosine;United States;Unsaturated Fatty Acids;Up-Regulation (Physiology);Vascular remodeling;vascular smooth muscle cell migration;Vitamins","PROJECT_TITLE":"Nitro-Fatty Acids and Nrf2 in Vascular Remodeling","SERIAL_NUMBER":"105114","STUDY_SECTION":"ZRG1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"5","TOTAL_COST":"515414","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8934588","ABSTRACT_TEXT":"No abstract provided","ACTIVITY":"P50","ADMINISTERING_IC":"CA","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"09/25/2014","BUDGET_START":"09/01/2014","BUDGET_END":"08/31/2015","CFDA_CODE":"","CORE_PROJECT_NUM":"P50CA180907","ED_INST_TYPE":"","FOA_NUMBER":"RFA-DA-13-003","FULL_PROJECT_NUM":"5P50CA180907-02","FUNDING_ICs":"NCI:314153\\","FUNDING_MECHANISM":"Research Centers","FY":"2014","IC_NAME":"NATIONAL CANCER INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"CHAPEL HILL","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"04","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIV OF NORTH CAROLINA CHAPEL HILL","ORG_STATE":"NC","ORG_ZIPCODE":"275990001","PHR":"","PI_IDS":"1871628;","PI_NAMEs":"RIBISL, KURT M.;","PROGRAM_OFFICER_NAME":"GINEXI, ELIZABETH M","PROJECT_START":"09/19/2013","PROJECT_END":"08/31/2018","PROJECT_TERMS":"abstracting;Adolescent;authority;Awareness;Bisexual;Characteristics;Collaborations;Communication;communication behavior;Communication Methods;design;Development;Electronics;Gays;Health;Health behavior;Health Communication;Hispanics;improved;Interdisciplinary Study;Intervention;Knowledge;Lesbian;Longevity;Participant;Perception;Printing;Protocols documentation;Research;Resource Sharing;Risk;Science;Services;Source;theories;Tobacco;tobacco control;Vulnerable Populations","PROJECT_TITLE":"Core C: Communication Core p267-282","SERIAL_NUMBER":"180907","STUDY_SECTION":"ZRG1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"7895","SUFFIX":"","SUPPORT_YEAR":"2","TOTAL_COST":"","TOTAL_COST_SUB_PROJECT":"314153"}
{"APPLICATION_ID":"8601161","ABSTRACT_TEXT":"This grant alms to understand the chemoattractant pathways that control the recruitment of Th2 effector  lymphocytes into the airways in human asthma. Since allergen-specific Th2 cells play a key role in the  pathogenesis of asthma, understanding the mechanisms that control their specific recruitment into the ain/vay  has the potential to lead to new more specific therapies for allergic asthma while leaving overall T cellmediated  lung immunity to viruses and other import human pathogens intact. In the 3.5 years of this R37  award, we have made significant progress towards this goal, and have also made some important related  discoveries concerning chemokine control of Treg trafficking into the allergic lung and the ability of lung  dendritic cells to imprint lung homing of T cells. In this project period, this grant has supported our work  resulting in 9 original publications (7 from the Pis laboratory), 6 reviews, 1 commentary and 2 book chapters.  In the prior funding period, we have identified CCR4 as an important chemokine receptor that participates in  the control of Th2 cell recruitment into the airways in asthma. We also found that Tregs are recrOited into the  lung in allergic pulmonary inflammation via a CCR4-dependent pathway where they have the ability to  s.uppress allergic pulmonary inflammation. Since CCR4 only accounts for -50% of the Th2 cell trafficking  signals, we clearly need to identify the other relevant chemoattractant pathways. In addition, since CCR4 is  also important for Treg cell recruitment into the lung, the identification of additional chemokine pathways that  participate in Th2 cells trafficking into the allergic lung could allow the specific targeting of Th2 cells, leaving  Treg recruitment intact. In the MERIT extension period we will generate a CCL17 and CCL22 dual reporter  mouse to determine the pattern of CCR4 ligand expression in the lung and lymph node in allergic pulmonary  inflammation. We will also image the influence of chemokines on Th2, Treg and DC interactions in the lung  using confocal and multiphtoton intravital microscopy. In addition, we will determine the chemokine  receptors responsible for lung-specific homing and identify the lung DC subset that imprints lung-specific  homing. In the prior funding period, our analysis of human T cells recruited into the airway following allergen  challenge was restricted to bulk T cells, which include many bystander T cells. In our extension period, we  will build upon our work using MHC class II allergen-specific tetramers to precisely define the chemokine  receptor phenotype of allergen-specific T cells recruited into the lung. This is very important because in  order to define the chemoattractant receptor pathways critical for pathogenic T cell recruitment into the  airway in asthma, we need to define the relevant pathway for the critical cell, the allergen-specific T cell.","ACTIVITY":"R37","ADMINISTERING_IC":"AI","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"11/26/2013","BUDGET_START":"12/01/2013","BUDGET_END":"11/30/2014","CFDA_CODE":"855","CORE_PROJECT_NUM":"R37AI040618","ED_INST_TYPE":"","FOA_NUMBER":"","FULL_PROJECT_NUM":"5R37AI040618-17","FUNDING_ICs":"NIAID:403476\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES","NIH_SPENDING_CATS":"","ORG_CITY":"BOSTON","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"07","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"MASSACHUSETTS GENERAL HOSPITAL","ORG_STATE":"MA","ORG_ZIPCODE":"021997603","PHR":"Asthma is an allergic disease of the lung that is increasing in prevalence and severity, especially among  children, despite current therapies. Asthma is caused by the inappropriate activation and accumulation of T  cells in the lung, where they drive the asthmatic response through the'release of potent inflammatory  mediators. The goal of this grant is to identify the key proteins that control the accumulation of these  pathogenic T cells in the lung, which will define excellent new targets for therapeutic intervention.","PI_IDS":"1901884;","PI_NAMEs":"LUSTER, ANDREW D;","PROGRAM_OFFICER_NAME":"MINNICOZZI, MICHAEL ","PROJECT_START":"01/01/1997","PROJECT_END":"11/30/2017","PROJECT_TERMS":"Accounting;Allergens;Allergic;Allergic Disease;Asthma;Award;Book Chapters;CC chemokine receptor 4;CCL17 gene;CCL22 gene;CCR8 gene;Cells;chemokine;chemokine receptor;Chemotactic Factors;Child;Critical Pathways;CXCR3 gene;Dendritic Cells;design;Extrinsic asthma;fMet-Leu-Phe receptor;Funding;Goals;Grant;Homing;Human;Image;Immune Cell Activation;Immunity;imprint;Inflammation Mediators;intravital microscopy;Laboratories;Lead;Left;Left lung;Ligands;Lung;lymph nodes;Lymphatic;Lymphocyte;MHC Class II Genes;Mus;Myeloid Cells;pathogen;Pathogenesis;Pathway interactions;Pattern;Phenotype;Play;Pneumonia;Prevalence;Proteins;Publications;Published Comment;Recruitment Activity;Regulatory T-Lymphocyte;Relative (related person);Reporter;response;Role;Severities;Signal Transduction;T-Lymphocyte;Th2 Cells;Therapeutic Intervention;trafficking;Virus;Work","PROJECT_TITLE":"Chemokines and Th2 Cell Trafficking in Asthma","SERIAL_NUMBER":"40618","STUDY_SECTION":"NSS","STUDY_SECTION_NAME":"No Study Section (in-house review)","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"17","TOTAL_COST":"403476","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8691819","ABSTRACT_TEXT":" Abstract Many environmental stressors have deleterious effects on mitochondrial functions, by a variety of mechanisms, and with timelines of different lengths. Mitochondrial dysfunction has multiple clinical presentations, often delayed from the onset of organelle damage. At present, biomarkers that report on mitochondrial function, to enable population studies of environmental exposures and their consequences, are lacking. We propose to identify candidate biomarkers using a metabolomics approach, in greater depth than has previously been applied to toxicologic investigations.  Metabolomic analysis provides a window on cellular and organismal functions, closer to the actual physiology than genomic or transcriptomic arrays. Using multiple platforms for separation and mass spectrometric resolution of complex mixtures, a comprehensive set of metabolites including organic acids, amino acids, steroids, complex lipids, energy charge and mitochondrial transport metabolites can be targeted. We will use this technology to develop biomarkers of mitochondrial dysfunction that will fill an important gap in current studies of environmental toxicology.  We will focus our studies on a polybrominated diphenyl ether, BDE-47, that is emerging as one of the major persistent organic pollutants in the U.S. Published data from our collaborator, Dr. Kavanagh, and our preliminary data indicate that BDE-47 impairs mitochondrial function in cell lines in vitro. Metabolites in extracellular media (metabolic footprinting) will be analyzed with primary mouse hepatocytes, one of the main targets of BDE-47 toxicity, as a function of dose and time of exposure. We will also test the hypothesis that fatty acid overload will uncover subtle mitochondrial defects by performing metabolomic analysis in isolated mitochondria. These studies will provide metabolic signatures of BDE-47 toxicity that will next be extended to in vivo studies of plasma and urine from BDE-47 treated mice. The possibility that lymphocytes may be a surrogate tissue for the mitochondrial toxicities of BDE-47 will be examined using the fatty acid overload assay.  The effects of genetic background and environment on BDE-47 toxicity are poorly understood. We will test two potential modifiers: 1) genetically engineered mice with low and high glutathione levels, and 2) fatty liver due to vitamin A deficiency. These experiments will provide novel information on potential high risk populations for BDE-47 exposure. A key question for these studies will be whether candidate biomarkers scale with toxicity (in addition to exposure dose).  In addition to discovering metabolic signatures of BDE-47 toxicity, we will examine two recently described mitochondrial responses to stress by metabolic footprinting: 1) mitochondrial proteotoxicity due to aggregation of unfolded/unassembled proteins, and 2) alternative fumarate respiration in response to hypoxia and distal block of the electron transport chain. By selecting defined mitochondrial responses, one adverse and one adaptive, we begin to categorize mitochondrial dysfunction and look for signatures that associate with specific types. In the case of fumarate respiration, a signature of high levels of succinate in secreted metabolites is already known.  This work is a close collaboration with Oliver Fiehn, expert in metabolomics screening and data analysis, and Terry Kavanagh, an expert in oxidative stress and mitochondrial toxicology.","ACTIVITY":"R01","ADMINISTERING_IC":"ES","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"06/18/2014","BUDGET_START":"07/01/2014","BUDGET_END":"06/30/2015","CFDA_CODE":"113","CORE_PROJECT_NUM":"R01ES020819","ED_INST_TYPE":"","FOA_NUMBER":"RFA-ES-11-007","FULL_PROJECT_NUM":"5R01ES020819-04","FUNDING_ICs":"NIEHS:373821\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES","NIH_SPENDING_CATS":"","ORG_CITY":"SEATTLE","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"FRED HUTCHINSON CANCER RESEARCH CENTER","ORG_STATE":"WA","ORG_ZIPCODE":"981091024","PHR":" Public Health Relevance/Project Narrative Many environmental toxins inhibit mitochondria, the powerhouses of the cell, as a mechanism of toxicity. Current research in this area is hampered by the lack of convenient tests to measure early mitochondrial damage, which would promote appropriate preventive/treatment efforts for individuals and at risk populations. The goal of this research is to identify chemical changes in blood or urine that are indicators of mitochondrial damage in the body, using mass spectrometry tools to survey thousands of compounds.","PI_IDS":"1936563;","PI_NAMEs":"HOCKENBERY, DAVID M.;","PROGRAM_OFFICER_NAME":"SHAUGHNESSY, DANIEL ","PROJECT_START":"09/21/2011","PROJECT_END":"06/30/2016","PROJECT_TERMS":"abstracting;Affect;Amino Acids;Area;base;Biochemical;Biochemistry;Bioenergetics;Biological Assay;Biological Markers;Biology;Blood;Body Fluids;Cell Line;Cell physiology;Cells;Characteristics;Charge;Chemicals;Classification;Clinical;Collaborations;Complex;Complex Mixtures;Data;Data Analyses;Defect;Diet;Disease;Distal;Dose;Electron Transport;Environment;Environmental Exposure;environmental stressor;environmental toxicology;Exhibits;Exposure to;extracellular;Fatty Acids;Fatty Liver;Fumarates;Functional disorder;Generations;Genetic;Genetically Engineered Mouse;Genomics;Glutathione;Goals;Harvest;Hepatocyte;high risk;Histocompatibility Testing;human population study;Hypoxia;In Vitro;in vivo;Individual;insight;Investigation;Length;Lipids;Liquid substance;Lymphocyte;Machine Learning;Mass Spectrum Analysis;Measures;Membrane Potentials;Metabolic;Metabolic stress;Metabolic syndrome;metabolomics;Methods;Mitochondria;Mitochondrial Diseases;mitochondrial dysfunction;Modeling;Mus;nonalcoholic steatohepatitis;novel;nucleotide metabolism;Organelles;organic acid;Oxidative Stress;phenyl ether;Physiology;Plasma;pollutant;Population;Population Study;Populations at Risk;Pre-Clinical Model;Preventive;protein misfolding;Proteins;public health relevance;Publishing;Reactive Oxygen Species;Reporting;Research;research study;Resolution;Respiration;response;screening;Staging;statistics;Steroids;Stress;Succinates;Surveys;Technology;Testing;Time;TimeLine;Tissues;tool;Toxic effect;Toxic Environmental Substances;toxicant;Toxicology;transcriptomics;Urine;Vitamin A;Vitamin A Deficiency;Work","PROJECT_TITLE":"Biomarker discovery for mitochondrial toxicants using metabolic footprinting","SERIAL_NUMBER":"20819","STUDY_SECTION":"ZES1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"4","TOTAL_COST":"373821","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8584229","ABSTRACT_TEXT":"Salivary gland function, repair, and regeneration are compromised after loss of parasympathetic innervation.  However, the role ofthe nerves in repair/regeneration remains poorly understood. The objective ofthis study  is to investigate the mechanisms of neuronal-epithelial communication between the submandibular gland  (SMG) and the parasympathetic submandibular ganglion during embryonic development. The specific aims  are to: 1) determine the mechanisms by which acetylcholine released from the neurons influences epithelial  morphogenesis, and 2) determine the mechanisms by which the neurotrophic growth factor neurturin, which  is secreted from the epithelium, influences neuronal function and epithelial morphogenesis. Goals include:  elucidating the signaling pathways activated by the nerves that govern epithelial progenitor ceil self-renewal  versus differentiation, investigating the influence of acetylcholine/musarinic/EGFR signaling on progenitor  cell migration and polarization, and identifying the mechanisms by which neurturin promotes both epithelial  and neuronal survival and regeneration after gamma radiation-induced injury. These goals will be achieved  using well-defined ex vivo SMG and organotypic culture models in conjunction with genetic, biochemical,  immunochemical, and fluorescence imaging techniques. These studies will facilitate our understanding of  how salivary glands develop, repair, and regenerate, with the long-term aim of providing therapeutic  approaches for re-establishing glandular structure and function after disease or injury.","ACTIVITY":"R00","ADMINISTERING_IC":"DE","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"12/23/2013","BUDGET_START":"01/01/2014","BUDGET_END":"12/31/2014","CFDA_CODE":"121","CORE_PROJECT_NUM":"R00DE018969","ED_INST_TYPE":"SCHOOLS OF DENTISTRY/ORAL HYGN","FOA_NUMBER":"","FULL_PROJECT_NUM":"5R00DE018969-04","FUNDING_ICs":"NIDCR:249000\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF DENTAL &CRANIOFACIAL RESEARCH","NIH_SPENDING_CATS":"","ORG_CITY":"SAN FRANCISCO","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"ANATOMY/CELL BIOLOGY","ORG_DISTRICT":"12","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF CALIFORNIA, SAN FRANCISCO","ORG_STATE":"CA","ORG_ZIPCODE":"941430962","PHR":"Both the function and regeneration of the salivary gland organ system are entirely dependent on innervation  by the autonomic nervous system. Little is known about the development or integration of the parasypathetic  submandibular ganglion into the glandular tissue. Understanding the nature of these interactions and the  factors involved will be essential to replacing and/or regenerating salivary glands after pathological gland  destruction, surgical removal, or salivary dysfunction.","PI_IDS":"9131154;","PI_NAMEs":"KNOX, SARAH MONICA;","PROGRAM_OFFICER_NAME":"MELILLO, AMANDA A","PROJECT_START":"01/24/2012","PROJECT_END":"12/31/2014","PROJECT_TERMS":"Acetylcholine;Autonomic nervous system;Biochemical;body system;cell motility;Communication;Development;Disease;Embryonic Development;Epidermal Growth Factor Receptor;Epithelial;Epithelium;Excision;fluorescence imaging;Functional disorder;Gamma Rays;Ganglia;Genetic;Gland;gland development;Goals;Growth Factor;Imaging Techniques;Injury;Modeling;Morphogenesis;Mus;Natural regeneration;Nature;Nerve;Nerve Regeneration;nerve supply;neuronal survival;Neurons;neurturin;progenitor;repaired;Role;Salivary;Salivary Glands;self-renewal;Signal Pathway;Signal Transduction;Stem cells;Structure;Submandibular gland;Therapeutic;Tissues","PROJECT_TITLE":"Neuronal-epithelial interactions that regulate mouse salivary gland development","SERIAL_NUMBER":"18969","STUDY_SECTION":"NSS","STUDY_SECTION_NAME":"No Study Section (in-house review)","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"4","TOTAL_COST":"249000","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8728960","ABSTRACT_TEXT":"PROJECT SUMMARY (See instructions):  Robust regeneration of tissues and complex organs is the norm for countless invertebrate and nonmammalian vertebrate species. In addition, nature has endowed certain animals with remarkable longevity and robust tissue repair mechanisms that slow aging-induced degenerative processes, or with increased susceptibility to cellular and molecular damage and concomitantly short lifespans. Numerous fundamental questions in regenerative biology can only be answered in vivo using diverse non-mammalian animal models. In addition, comparative studies of diverse organisms provide deeper mechanistic insights that are not possible using a single model or \"model-centric\" approach, and they can speed the pace and reduce the cost of biomedical discovery. The Comparative Animal Models Core builds on MDIBL's unique strength and expertise in comparative animal biology and will provide COBRE investigators with resources necessary to utilize diverse animal models in regenerative and aging biology research. For the current application, the Core focuses primarily on providing resources and services to COBRE Project Leaders for their proposed zebrafish studies. These resources include day-to-day husbandry, importation and quarantine services, spawning services to produce embryos for experimental studies, microinjection and surgical services, drug treatment services and genotyping using visual inspection and PCR-based methods. The Core will also have both the facilities and expertise necessary to provide COBRE associated investigators as well as potential new COBRE Project Leaders with resources for other vertebrate and invertebrate model systems useful in regenerative and aging biology research including C. elegans, amphibians and various fish species.  Our long term goal is to develop the Core into a one-of-a-kind animal resource by leveraging the scientific background and expertise of the Core Director, his staff and MDIBL's faculty, as well as MDIBL's 113-year history of providing and maintaining diverse marine organisms for biomedical research. The Comparative Animal Models Core will thus contribute not only to the success and long term sustainability of the COBRE, but also to the success and continued growth of MDIBL and biomedical research in Maine.","ACTIVITY":"P20","ADMINISTERING_IC":"GM","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"05/29/2014","BUDGET_START":"06/01/2014","BUDGET_END":"05/31/2015","CFDA_CODE":"","CORE_PROJECT_NUM":"P20GM104318","ED_INST_TYPE":"","FOA_NUMBER":"PAR-11-286","FULL_PROJECT_NUM":"5P20GM104318-02","FUNDING_ICs":"NIGMS:215196\\","FUNDING_MECHANISM":"Research Centers","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES","NIH_SPENDING_CATS":"","ORG_CITY":"SALSBURY COVE","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"02","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"MOUNT DESERT ISLAND BIOLOGICAL LAB","ORG_STATE":"ME","ORG_ZIPCODE":"046720035","PHR":"RELEVANCE (See instructions):  Numerous fundamental questions in regenerative biology can only be answered in vivo using diverse non mammalian animal models. Non-mammalian animal studies also speed the pace and reduce the cost of biomedical discovery. The Comparative Animal Models Core provides comprehensive resources required for the use of diverse non-mammalian model organisms in regenerative biology and medicine research.","PI_IDS":"10569834;","PI_NAMEs":"WRAY, CHARLES G;","PROGRAM_OFFICER_NAME":"","PROJECT_START":"","PROJECT_END":"","PROJECT_TERMS":"Address;Aging;Amphibia;Animal Experimentation;animal facility;Animal Model;animal resource;Animals;base;Behavioral;Biological Models;Biological Process;Biology;Biology of Aging;Biomedical Research;Caenorhabditis elegans;Cell Culture Techniques;Centers of Research Excellence;Collaborations;comparative;Comparative Biology;Comparative Study;Complement;Complex;cost;Embryo;Faculty;Fishes;Fundulus;Future;Genotype;Goals;Growth;Housing;human disease;in vivo;innovation;insight;Instruction;Invertebrates;Longevity;Maine;Maintenance;Mammalian Cell;marine organism;Marines;Medicine;Methods;Microinjections;Modeling;Molecular;Mus;Natural regeneration;Nature;Organ;Organism;Pharmaceutical Preparations;Predisposition;Process;Quarantine;Recording of previous events;regenerative;Research;Research Infrastructure;Research Personnel;research study;Resources;Scientist;Sea Urchins;Services;Speed (motion);square foot;success;surgical service;The Jackson Laboratory;Tissue Harvesting;tissue regeneration;tissue repair;Transgenic Organisms;Visit;Visual;Xenopus;Yin;Zebrafish","PROJECT_TITLE":"COMPARATIVE ANIMAL MODELS CORE","SERIAL_NUMBER":"104318","STUDY_SECTION":"ZGM1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"8249","SUFFIX":"","SUPPORT_YEAR":"2","TOTAL_COST":"","TOTAL_COST_SUB_PROJECT":"215196"}
{"APPLICATION_ID":"8631055","ABSTRACT_TEXT":"   DESCRIPTION (provided by applicant): The goal of this project is to identify the molecular alterations that occur in the progression from ductal carcinoma in situ (DCIS) to invasive breast cancer. This is of critical importance because it is only after the milestone of tissue invasion has been achieved that a cancer has the potential to metastasize and kill a patient. Invasive breast cancers harbor multiple molecular alterations that were sequentially acquired during progression from ADH to ductal carcinoma in situ (DCIS) to invasive breast cancer. We will identify the genetic alterations that may be specific to DCIS or may be cumulative with increasing malignant potential. 7Rationale: While the cure rate for ductal carcinoma in situ (DCIS) is over 90%, this comes at the cost of considerable treatment-related morbidity. We urgently need the prognostic markers that would identify key genetic alterations predictive of the long-term outcome of DCIS, since most DCIS never become invasive carcinomas, presumably because they lack critical genetic changes, the replicative lifespan, or simply the time necessary to do so. Our experimental design exploits recent technological developments that permit genome- wide testing of DNA samples for genetic and epigenetic alterations, even in the very limited material available from archival DCIS samples. DCIS may represent a stage at which various pathways of clonal evolution are attempted, until a particular combination of genetic and/or epigenetic changes allows tissue invasion. Indications are that genetic mutations and epigenetic silencing may both be operative in carcinogenesis, and that these alternatives may be used interchangeably, even in a complementary fashion in the same cancer cell. Therefore, a combined analysis of both types of alterations is necessary. 7Design: This study is designed as multicenter, longitudinal, case-control study of DCIS. We have identified unique cohorts of pure DCIS cases with known outcomes to enable a multicenter genome-wide screening study of 100 cases and 100 controls, which will be initially limited to patients of Caucasian origin in order to obtain a homogenous patient population and maximize the probability of successfully validating our hypothesis that prognostic markers exist in DCIS. Candidate markers of interest will be further characterized by quantitative PCR methods, with the goal of creating a single, prognostic multiplex PCR signature that can be used on the limited clinical material typically obtained in the diagnostic phase of the evaluation of DCIS. We will then validate the assay in an independent test cohort of 100 cases of DCIS with progressive disease vs. 100 cases of DCIS that remain disease free, obtained from the population-based repository provided by the Iowa SEER residual tissue repository (RTR). We will also use an additional population-based repository located in Hawaii, to test if the prognostic signature developed from Caucasian samples can be used successfully in a different ethnic group. This will guide future work, particularly regarding the necessity of exploring the predictive power of the multiplex assay in different populations.      ","ACTIVITY":"R01","ADMINISTERING_IC":"CA","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"03/27/2014","BUDGET_START":"04/01/2014","BUDGET_END":"03/31/2015","CFDA_CODE":"393","CORE_PROJECT_NUM":"R01CA140311","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"PA-10-067","FULL_PROJECT_NUM":"5R01CA140311-04","FUNDING_ICs":"NCI:486308\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL CANCER INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"BALTIMORE","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"SURGERY","ORG_DISTRICT":"07","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"JOHNS HOPKINS UNIVERSITY","ORG_STATE":"MD","ORG_ZIPCODE":"212182608","PHR":"PUBLIC HEALTH RELEVANCE: The overarching goal of this project is to develop robust, DNA-based predictive genetic markers that will be useful in identifying the minority of cases of preinvasive breast cancer (DCIS), that do in fact progress to invasive disease, given the current lack of molecular guidance available to stratify patients with pure DCIS. Of the over 60,000 women currently diagnosed with pure DCIS per year, less than 30% will develop recurrent breast disease within 10 years of undergoing a surgical resection. With appropriate markers, many could be spared the cost and morbidity of aggressive therapy. Furthermore, the assessment of new approaches to better treat those patients at high risk of disease progression will remain problematic as long as most cases would do well regardless of intervention.         ","PI_IDS":"1926860;","PI_NAMEs":"UMBRICHT, CHRISTOPHER B;","PROGRAM_OFFICER_NAME":"ZANETTI, KRISTA A","PROJECT_START":"04/19/2011","PROJECT_END":"03/31/2016","PROJECT_TERMS":"aggressive therapy;base;Bioinformatics;Biological Assay;Biological Markers;Breast Diseases;cancer cell;candidate marker;carcinogenesis;Carcinoma;Case-Control Studies;Cataloging;Catalogs;Caucasians;Caucasoid Race;Clinical;Clinical Management;clinical material;Clonal Evolution;cohort;Copy Number Polymorphism;cost;Data;design;Development;Diagnosis;Diagnostic;Disease;Disease Progression;Disease-Free Survival;DNA;DNA Methylation;Ensure;Epigenetic Process;Ethnic group;Evaluation;Event;Excision;Experimental Designs;Formalin;Future;Gene Mutation;Genes;Genetic;Genetic Markers;genome wide association study;genome-wide;genome-wide analysis;Genomics;Goals;Hawaii;high risk;high throughput analysis;Housing;interest;Intervention;Iowa;Killings;Location;Longevity;Loss of Heterozygosity;Malignant - descriptor;malignant breast neoplasm;Malignant Neoplasms;Medical Surveillance;Methods;Methylation;Minority;Modeling;Molecular;Morbidity - disease rate;Mutation;National Cancer Institute;Neoplasm Metastasis;Noninfiltrating Intraductal Carcinoma;novel strategies;Operative Surgical Procedures;Outcome;Paraffin Embedding;Pathway interactions;patient population;Patients;Pattern;Performance;performance tests;Phase;Population;population based;Probability;prognostic;Prognostic Marker;Progressive Disease;public health relevance;Quality of life;racial and ethnic;Recurrence;Recurrent disease;repository;Residual state;Resolution;Sampling;Screening for cancer;Staging;success;Testing;Therapeutic;Time;Tissue Sample;Tissue-Specific Gene Expression;Tissues;Treatment Cost;Validation;Woman;Work","PROJECT_TITLE":"Multicenter Genetic, Epigenetic &Expression Analysis of DCIS outcome predictors","SERIAL_NUMBER":"140311","STUDY_SECTION":"CBSS","STUDY_SECTION_NAME":"Cancer Biomarkers Study Section","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"4","TOTAL_COST":"486308","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8889398","ABSTRACT_TEXT":"The goal of the Gene-Environment Interactions Training Program (GEITP) is to train pre-doctoral and postdoctoral students who will be versed in ways that both environment exposures and genetic diversity nteract to alter the onset of disease. Achieving this objective requires an interdisciplinary team approach integrating an understanding of genetic diversity, epigenetic alterations, high-throughput genomics, biostatistics, biomarkers, and exposure assessment approaches. The collaborative efforts of research faculty, clinicians, postdoctoral and pre-doctoral trainees are needed in order to meet this objective. A mentorship team approach, combining the expertise of well-regarded scientists in the areas of exposure assessment, genetic variability, biomarkers of disease, and individualized/tailored medicine will be used to educate trainees in multiple areas of gene-environment interactions. Predoctoral training will include required coursework in addition to the student's matriculated Ph.D. program, laboratory rotations with the team of mentors, and hands-on work in several areas of exposure assessment, high-throughput genetic variability measures, and biomarkers or exposure and/or disease. Postdoctoral training will include programs in laboratory and personnel management, pilot grant applications, and an intensive year long grant writing workshop to prepare them for independent research. All trainees will be required to attend \"Technologies in genomics, exposure, and biomarkers\" workshop, which will be created as part of this program, and present research results at an annual GEITP Student Symposium. This program will include a dedicated governance structure to assure that appropriate trainees are recruited, education goals are met, and the aims of this grant are achieved.","ACTIVITY":"T32","ADMINISTERING_IC":"ES","APPLICATION_TYPE":"3","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"07/11/2014","BUDGET_START":"07/01/2014","BUDGET_END":"06/30/2015","CFDA_CODE":"113","CORE_PROJECT_NUM":"T32ES016646","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"RFA-ES-07-002","FULL_PROJECT_NUM":"3T32ES016646-05S1","FUNDING_ICs":"NIEHS:256447\\","FUNDING_MECHANISM":"Training, Institutional","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES","NIH_SPENDING_CATS":"","ORG_CITY":"CINCINNATI","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"PUBLIC HEALTH &PREV MEDICINE","ORG_DISTRICT":"01","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF CINCINNATI","ORG_STATE":"OH","ORG_ZIPCODE":"452210001","PHR":"","PI_IDS":"1867525;","PI_NAMEs":"PUGA, ALVARO;","PROGRAM_OFFICER_NAME":"SHREFFLER, CAROL K","PROJECT_START":"07/01/2008","PROJECT_END":"06/30/2015","PROJECT_TERMS":"Environment;Genes;Training Programs","PROJECT_TITLE":"Gene-Environment Interactinos Training Program","SERIAL_NUMBER":"16646","STUDY_SECTION":"ZES1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"S1","SUPPORT_YEAR":"5","TOTAL_COST":"256447","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8750650","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): The overarching goal of this proposal is to identify key methylation marks that regulate expression of mRNAs and miRNAs involved in pathogenesis of idiopathic pulmonary fibrosis (IPF). IPF is an untreatable and often fatal lung disease that is increasing in prevalence and is likely the result of complex interactions between genetic and environmental factors such as cigarette smoke. Although it is currently believed that the injury to the alveolar epithelium initiates a cascade of events that lead to accumulation of extracellular matrix, dysregulated wound repair, and lung remodeling, dramatic changes in mRNA and miRNA expression changes and cellular phenotypes in IPF lung suggest that many different molecular processes are involved. Several lines of evidence support the role of epigenetic regulation of gene expression in IPF lung. Firstly, recent studies have demonstrated that cigarette smoke, a key environmental risk factor for IPF, has an influence on the epigenome and on methylation of specific promoters in genes involved in pathogenesis of IPF. Secondly, IPF is a genetic disease, and genetic factors influence DNA methylation. Thirdly, focused studies to date have demonstrated the influence of epigenetic marks on expression of key genes in IPF. Fourthly, data are emerging on the role of DNA methylation in regulation of miRNA expression in IPF. Finally, our recent work demonstrates extensive methylation changes on the genomic scale in IPF lung. The hypothesis of this proposal is that DNA methylation marks regulate expression of key fibrotic mRNAs and miRNAs in the IPF lung. We will test this hypothesis using existing Lung Genomics Research Consortium (LGRC), ENCyclopedia Of DNA Elements (ENCODE) and Roadmap Epigenomics (RE) project data. We will first perform methyl-expression quantitative trait locus (me-eQTL) mapping to identify differentially methylated regions (DMRs) that control mRNAs and miRNA expression as well as mRNA alternative splicing in cis and trans in IPF lung tissue. We will then prioritize the DMRs based on their regulatory potential in the lung using available ENCODE and RE methylation, histone mark, transcription factor binding, and chromatin accessibility data in lung tissue, relevant primary cells and cell lines. Results of this work will be used as preliminary data for a R01 application that will explore the influence of cigarette smoke and genetic variants on identified methylation marks and will perform functional studies to determine how treatment with agents that alter methylation marks influence expression of target mRNAs and miRNAs as well as fibro-proliferative phenotypes in vitro and in vivo.        ","ACTIVITY":"R21","ADMINISTERING_IC":"HL","APPLICATION_TYPE":"1","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"07/15/2014","BUDGET_START":"08/01/2014","BUDGET_END":"04/30/2015","CFDA_CODE":"837","CORE_PROJECT_NUM":"R21HL121572","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"PAR-13-009","FULL_PROJECT_NUM":"1R21HL121572-01A1","FUNDING_ICs":"NHLBI:116250\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL HEART, LUNG, AND BLOOD INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"AURORA","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"INTERNAL MEDICINE/MEDICINE","ORG_DISTRICT":"06","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF COLORADO DENVER","ORG_STATE":"CO","ORG_ZIPCODE":"800452570","PHR":"PUBLIC HEALTH RELEVANCE: Idiopathic pulmonary fibrosis (IPF) is an untreatable and often fatal lung disease that is increasing in prevalence and is likely the result of complex interaction between genetic and environmental factors such as cigarette smoke. The purpose of this proposal is to integrate existing data from multiple consortia to identify DNA methylation marks that control expression of genes and miRNAs involved in pathogenesis of IPF. The discovery of key epigenetic marks is likely to lead to a new way of treating pulmonary fibrosis as changes to a gene's methylation can be reversed, and reversal of methylation marks can lead to changes in expression.                ","PI_IDS":"9643510;","PI_NAMEs":"YANG, IVANA VERONA;","PROGRAM_OFFICER_NAME":"EU, JERRY PC","PROJECT_START":"08/01/2014","PROJECT_END":"04/30/2016","PROJECT_TERMS":"Alternative Splicing;Alveolar;alveolar epithelium;Azacitidine;base;Binding (Molecular Function);Biochemical;Bioinformatics;Biological Process;Cell Line;cell type;Cells;chemokine;Chromatin;Cigarette;cigarette smoke;Complex;cyclooxygenase 2;Data;Data Set;Decitabine;Development;Disease;DNA;DNA Methylation;Elements;Environmental Risk Factor;Epigenetic Process;epigenome;epigenomics;Epithelial;Epithelial Cells;Event;Extracellular Matrix;Fibroblasts;Folic Acid Antagonists;Future;Gene Expression;Gene Expression Profiling;Gene Expression Regulation;Genes;Genetic;genetic variant;Genome;Genomics;Genotype;Goals;Hamman-Rich syndrome;Hereditary Disease;Histocompatibility Testing;Histones;Human Genome;In Vitro;in vivo;Individual;injured;Injury;Lead;Lung;Lung diseases;Malignant Neoplasms;Maps;Mediator of activation protein;Mesenchymal;Messenger RNA;Methylation;MicroRNAs;Molecular;mRNA Expression;Non-Malignant;Nucleic Acid Regulatory Sequences;Open Reading Frames;Pathogenesis;Pathway interactions;Phenotype;Prevalence;Process;Promotor (Genetics);public health relevance;Publications;Pulmonary Fibrosis;Quantitative Trait Loci;Regulation;Regulatory Element;Relative (related person);Research;RNA Splicing;Role;Smooth Muscle Actin Staining Method;Structure of parenchyma of lung;Testing;transcription factor;Variant;Work;Wound Healing","PROJECT_TITLE":"Regulation of mRNA and miRNA Expression in Pulmonary Fibrosis by DNA Methylation","SERIAL_NUMBER":"121572","STUDY_SECTION":"ZRG1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"A1","SUPPORT_YEAR":"1","TOTAL_COST":"116250","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8695296","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): Since its inception in 1992, The University of Texas MD Anderson Cancer Center Cancer Prevention Education: Student Research Experiences (the Program, www.cancerpreventiontraining.org) has had as its objective to provide short-term research experiences in cancer prevention research and education to students as a means to recruit them to careers in cancer prevention research. We have developed curriculum- based methods that provide new knowledge and opportunities for undergraduate and graduate students from the basic biomedical sciences, biostatistics, epidemiology, genetics, behavioral and social sciences, nursing, medicine, and related public health disciplines to conduct mentored research. Beginning with 10 positions in 1992 and increasing over time, the Program now support 25 positions annually. To date, all positions have been filled annually. The Advisory Committee reviews and selects the students based on the merit of their academic performance, educational objectives, and research interests. Students receive a stipend with limited funds available for tuition for required courses, Topics in Cancer Prevention I &II and Bio-behavioral Research Methods in Cancer Prevention and Addiction. Students deliver oral reports on their research experience at our Cancer Prevention Trainee Brown Bag seminars. The Specific Aims are to provide 25 high-performing students with 10-15-week experiences in cancer prevention annually;to cultivate faculty mentors and to recognize model mentors;to conduct innovative and effective recruitment and application processes, with particular attention to attracting a demographically diverse population;to engage the Advisory Committee in the continuous program improvement;to provide up-to-date and highly relevant multi-disciplinary curriculum in cancer prevention and cancer prevention careers;and to rigorously evaluate the Program and follow long-term career development of trainees. Several innovations are proposed: 1) launch of a personalized career exploration and development series, \"Prevention Parachute;\" 2) a major overhaul of the Cancer Prevention Educational Curriculum by renovating the \"Topics in Cancer Prevention\" series;3) using live web conferencing with cancer prevention scientists and sister R25E programs elsewhere for enhancing engagement in new directions in cancer prevention;and 4) addition of a seminar series that showcases individuals in specific careers and their paths within the field as real-life examples for students. Overall, the Program's success takes many forms, from recruitment of a highly diverse student population, to students'development of master's theses and doctoral dissertations based on their research, to regularly taught graduate-level courses in cancer prevention, as well as the growing number of alumni who have completed training and currently hold academic positions in cancer prevention research.        ","ACTIVITY":"R25","ADMINISTERING_IC":"CA","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"09/04/2014","BUDGET_START":"07/01/2014","BUDGET_END":"06/30/2015","CFDA_CODE":"398","CORE_PROJECT_NUM":"R25CA056452","ED_INST_TYPE":"OVERALL MEDICAL","FOA_NUMBER":"PAR-12-049","FULL_PROJECT_NUM":"5R25CA056452-22","FUNDING_ICs":"NCI:271416\\","FUNDING_MECHANISM":"Other Research Related","FY":"2014","IC_NAME":"NATIONAL CANCER INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"HOUSTON","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"NONE","ORG_DISTRICT":"09","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF TX MD ANDERSON CAN CTR","ORG_STATE":"TX","ORG_ZIPCODE":"770304009","PHR":"PUBLIC HEALTH RELEVANCE: This revised competitive renewal application for years 21 to 25 of an R25E award at The University of Texas MD Anderson Cancer Center, Cancer Prevention Education: Student Research Experiences (the Program, www.cancerpreventiontraining.org), requests support for students in (25) 10-15-week educational experiences per year for 5 years in multidisciplinary mentored cancer prevention research and career development. The Program recruits graduate and undergraduate students from the basic biomedical sciences, biostatistics, epidemiology, genetics, behavioral and social sciences, nursing, medicine, and related public health disciplines. The overall educational objective is to provide short-term research experiences in cancer prevention research to students as a means of recruiting them to careers in cancer prevention research.            ","PI_IDS":"1889453;","PI_NAMEs":"CHANG, SHINE;","PROGRAM_OFFICER_NAME":"KORCZAK, JEANNETTE F","PROJECT_START":"07/03/2013","PROJECT_END":"06/30/2018","PROJECT_TERMS":"Adopted;Advisory Committees;Appointment;Area;Attention;Authorship;Award;base;Behavioral Research;behavioral/social science;Biometry;cancer addiction;Cancer Control Research;Cancer Education Grant Program;cancer prevention;career;career development;cohort;Committee Members;design;Development;Discipline;Discipline of Nursing;Division of Cancer Prevention;Educational Activities;Educational Curriculum;Educational process of instructing;Effectiveness;Eligibility Determination;experience;Faculty;Family;feeding;Funding;genetic epidemiology;graduate student;Hawks;Individual;innovation;Institution;interest;Internet;Knowledge;Letters;Life;Malignant Neoplasms;Mediation;Medical;Medicine;Mentors;Methods;Modeling;multidisciplinary;Oral;Parachuting;Performance;Play;Population;Population Heterogeneity;Population Sciences;Positioning Attribute;Prevention;Prevention education;Prevention Research;Process;professor;programs;Progress Reports;public health medicine (field);Public Health Nurses;Public Health Nursing;public health relevance;Publications;Qualifying;Recruitment Activity;Reporting;Research;research and development;Research Methodology;Research Project Grants;Role;Schools;Science;Scientist;Series;Sister;Structure;Students;success;Time;tool;Training;Training Programs;undergraduate student;Underrepresented Minority;University of Texas M D Anderson Cancer Center;Work","PROJECT_TITLE":"Cancer Prevention Education: Student Research Experiences","SERIAL_NUMBER":"56452","STUDY_SECTION":"NCI","STUDY_SECTION_NAME":"Subcommittee B - Comprehensiveness","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"22","TOTAL_COST":"271416","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8708483","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): Cutaneous leishmaniasis (CL) has a long history in West Africa, but one of the less recognized parasitic infections in the region. The disease is endemic Saharan desert countries in the North, in Sahelian band from west to East Africa. Currently, there is no vaccine against the diseases. However, studies have consistently shown that sand fly saliva generally enhances infectivity of Leishmania parasites in a naive host while an adaptive immune response to whole saliva or a distinct salivary protein generally protects against both cutaneous and visceral leishmaniasis in rodent models of infection. In the proposed work, 3 sites in West Africa each with distinct epidemiological and ecological environment will be compared with regard to intensity and prevalence of cutaneous leishmania infection, sand fly vector population dynamics, and disease pathogenesis with a focus on parasite and host factors and the immune response to candidate vaccines (sand fly proteins in particular). The hypothesis underlying this proposal is that a combination of parasite, vector, and human exposure to other parasitic infection such as infection with microfilariae determine the immunomodulatory effects of candidate vaccines, specifically sand fly proteins. The proposal seeks to 1] understand the basic epidemiology of cutaneous leishmaniasis and its vector in different foci of West Africa;2] understand mechanism of resistance/susceptibility to the disease;3] assess how an active infection with microfilariae alters the human immune response to sand fly salivary proteins and 4] reinforce local research capacity for future vaccine trials.        RELEVANCE: This proposal is directly relevant to public health because Leishmaniasis take an enormous toll across the globe. Its goals are to examine the epidemiology, transmission of cutaneous leishmaniasis and a component that has been largely overlooked: the immuno-modulation of sandfly proteins.            Project 1: Epidemiology of Cutaneous Leishmaniasis    Project Leader: Ousmane Faye, MD, PhD    (Description as provided by applicant): Leishmaniasis is a vector-borne disease transmitted to the host via the bite of a Leishmania infected phlebotomine sand fly. Cutaneous leishmaniasis (CL) has a long history in West Africa, but is one of the less recognized parasitic infections in the region. Studies have consistently shown that sand fly saliva generally enhances infectivity of Leishmania parasites in a naive host while an adaptive immune response to whole saliva or a distinct salivary protein generally protects against both cutaneous and visceral leishmaniasis in rodent models of infection. In the proposed work, three sites in West Africa each with distinct epidemiological and ecological environment will be compared with regard to intensity and prevalence of cutaneous leishmania infection, sand fly vector population dynamics, and disease pathogenesis with a focus on parasite and host factors and the immune response to candidate vaccines (sand fly proteins in particular). This project seeks to 1] Determine the prevalence/incidence (of infection and disease) of CL and characterize the Leishmania parasites circulating in Malian and Ghanaian classical and cryptic foci of CL;2] Correlate specific human immune responses to sand fly salivary proteins with CL outcome. In the Aim 1 we will possibly characterize new species of Leishmania parasites from a site where the infected individuals presented with asymptomatic CL and compare it to a classical CL focus. We will also in Aim 2, for the first time, establish if sand fly salivary cellular immunity can influece the CL outcome in endemic populations.        RELEVANCE: This project is at the center of the entire proposal because it will assess the relationship between human exposure to sand fly vector bite (Project 2), the parasite and immune response to sand fly salivary proteins (Project 3) and the disease. Understanding of these relationship is important for vaccine development and field trials of control strategies.            ","ACTIVITY":"P50","ADMINISTERING_IC":"AI","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"07/22/2014","BUDGET_START":"08/01/2014","BUDGET_END":"07/31/2015","CFDA_CODE":"855","CORE_PROJECT_NUM":"P50AI098505","ED_INST_TYPE":"","FOA_NUMBER":"RFA-AI-11-001","FULL_PROJECT_NUM":"5P50AI098505-03","FUNDING_ICs":"NIAID:370000\\","FUNDING_MECHANISM":"Research Centers","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES","NIH_SPENDING_CATS":"","ORG_CITY":"BAMAKO","ORG_COUNTRY":"MALI","ORG_DEPT":"","ORG_DISTRICT":"","ORG_DUNS":"","ORG_FIPS":"ML","ORG_NAME":"UNIV OF SCIENCES, TECH &TECH OF BAMAKO","ORG_STATE":"","ORG_ZIPCODE":"","PHR":"","PI_IDS":"10128727;","PI_NAMEs":"DOUMBIA, SEYDOU;","PROGRAM_OFFICER_NAME":"RAO, MALLA R.","PROJECT_START":"08/01/2012","PROJECT_END":"07/31/2017","PROJECT_TERMS":"Affect;Africa;African;Antibodies;Antigen-Presenting Cells;Area;base;Biological Markers;Bite;Cells;Cellular Immunity;combat;control trial;Country;Cutaneous;Cutaneous Leishmaniasis;Data;Dendritic Cells;design;Development;Disease;Disease Vectors;Doctor of Philosophy;Drug Formulations;Environment;Environmental Risk Factor;Epidemiologic Studies;Epidemiology;exposed human population;Exposure to;field study;fly;Future;Ghana;Goals;Human;Immune;Immune response;Immunity;immunogenic;In Vitro;in vivo;Incidence;Individual;Infection;Integration Host Factors;Knowledge;Laboratories;Leishmania (genus);Leishmaniasis;Life;macrophage;Mali;Microfilaria;Molecular Profiling;monocyte;neglect;novel;Outcome;Parasites;Parasitic infection;pathogen;Pathogenesis;Phlebotominae;Phlebotomus (genus);Population;Population Dynamics;Predisposition;Prevalence;prevent;Proteins;public health medicine (field);Recording of previous events;Research;Resistance;resistance mechanism;Rodent Model;Role;Saliva;Salivary;Salivary Proteins;Sampling;Sand Flies;Scientist;Seasonal Variations;Site;Structure;success;T cell response;Testing;Time;tool;Training;transmission process;vaccine candidate;vaccine development;Vaccines;vector;Vector-transmitted infectious disease;Visceral Leishmaniasis;Work","PROJECT_TITLE":"Cutaneous Leishmaniasis in West Africa: the Parasite, Vector and Disease","SERIAL_NUMBER":"98505","STUDY_SECTION":"ZAI1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"3","TOTAL_COST":"370000","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8593272","ABSTRACT_TEXT":"DESCRIPTION (provided by applicant): Retinoblastoma is a malignant pediatric tumor in which mutations in the RB gene occur in the vast majority of cases. While retinoblastoma is initiated by RB inactivation, the steps between RB loss and tumorigenesis are not well understood. This proposal aims to investigate the changes that occur as retinoblastomas initiate and progress to malignancy. Mechanisms of cooperation with RB deletion in retinoblastoma may be broadly relevant for many human cancers. I hypothesize that secondary alterations help the retinoblastoma cell of origin evade a pathway to cell cycle exit controlled by the Rb family member, p130. These secondary alterations may alter the activity of p130 through control of cyclin dependent kinases (CDKs) or may act at other points in the pathway (e.g. by regulating E2F transcription factors). Moreover, I hypothesize that evasion of p130-controlled cell cycle exit in RB-deficient cells may be important not only for retinoblastoma, but for other tumor types. To test these hypotheses, we will use a combination of mouse genetics, cell culture studies and investigation of primary human and murine tumor samples. These studies will use the power of mouse models to determine definitively whether candidate Rb-cooperating genes are important for tumorigenesis and to understand how these co-operating genes synergize with Rb loss. Specific Aim 1: Investigate the mechanism by which Arf functions as tumor suppressor gene in retinoblastoma. Specific Aim 2: Assess whether N-myc alters the activity of the pRB family members in promoting tumorigenesis. This work has important implications for understanding many human tumor types that exhibit RB pathway inactivation. If pathways controlled by RB family members are functionally inactivated through secondary alterations, then reactivation of such pathways may provide new opportunities for therapeutic intervention.","ACTIVITY":"R01","ADMINISTERING_IC":"CA","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"11/25/2013","BUDGET_START":"01/01/2014","BUDGET_END":"12/31/2014","CFDA_CODE":"396","CORE_PROJECT_NUM":"R01CA148867","ED_INST_TYPE":"","FOA_NUMBER":"PA-07-070","FULL_PROJECT_NUM":"5R01CA148867-06","FUNDING_ICs":"NCI:386570\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL CANCER INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"SEATTLE","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"FRED HUTCHINSON CANCER RESEARCH CENTER","ORG_STATE":"WA","ORG_ZIPCODE":"981091024","PHR":"PUBLIC HEALTH RELEVANCE: The RB gene is deleted in many human tumors and the RB pathway is disrupted in virtually every human cancer. Certain cells in the developing retina are exquisitely sensitive to retinoblastoma upon RB gene mutation making retinoblastoma an ideal system to understand mechanisms behind cooperation with RB loss in tumorigenesis. We use mouse models and studies of human retinoblastoma samples to learn how RB- cooperating genes contribute to cancer.","PI_IDS":"9856130;","PI_NAMEs":"MACPHERSON, DAVID;","PROGRAM_OFFICER_NAME":"HILDESHEIM, JEFFREY ","PROJECT_START":"08/12/2010","PROJECT_END":"12/31/2014","PROJECT_TERMS":"CDKN2A gene;Cell Culture Techniques;Cell Cycle;Cell Cycle Regulation;Cell Line;Cells;Cyclin-Dependent Kinase Inhibitor;Cyclin-Dependent Kinases;Data;E2F transcription factors;Event;Exhibits;Family member;Gene Mutation;Gene Targeting;Genes;Genetic;Health;Human;in vivo;insight;Investigation;Lead;Learning;lung small cell carcinoma;Malignant Childhood Neoplasm;Malignant Neoplasms;Mediating;Molecular;mouse model;Mus;Mutation;novel;Oncogenic;Pathway interactions;Primary Neoplasm;Property;Recurrence;Regulation;Reporting;research study;Retina;Retinoblastoma;Retinoblastoma Protein;Sampling;Signal Transduction;System;Testing;Therapeutic Intervention;tumor;Tumor Cell Line;Tumor Suppressor Genes;Tumor Tissue;tumorigenesis;Work","PROJECT_TITLE":"Using mouse models to understand retinoblastoma initiation and progression","SERIAL_NUMBER":"148867","STUDY_SECTION":"CG","STUDY_SECTION_NAME":"Cancer Genetics Study Section","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"6","TOTAL_COST":"386570","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8588345","ABSTRACT_TEXT":"DESCRIPTION (provided by applicant): Cardiovascular disease remains the leading cause of death and disability in the USA and stiffening of central arteries is now an unquestioned independent risk factor for many such diseases, including heart attack, stroke, and end-stage renal disease. The six primary determinants of the structural stiffness of arteries are elastic fiber integrity, collagen organization, smooth muscle tone, wall thickness, axial pre-stretch, and perivascular support, each of which has a molecular and cellular basis and affects system-level hemodynamics. Easily measured clinical metrics, such as pulse wave velocity, can and must play an increasingly greater role in cardiovascular risk assessment, but we must understand much better the mechanical and biological basis for changes in such metrics. For example, the relation between pulse wave velocity and arterial stiffness is often justified based on the Moens-Korteweg equation, which ignores almost all of the key determinants of wall stiffness. Our approach is unique because we will be the first to combine genetically modified mouse models and pharmacological interventions to delineate directly the effects on the material stiffness of the wall due to the integrity of elastic fibers, organization of collagen fibers, and contractility of smooth muscle. Moreover, this information will be incorporated within a novel computational tool that will allow effects of axial prestretch, perivascular support, and most importantly spatially and temporally progressive changes in large artery wall composition on hemodynamic metrics to be rigorously assessed for the first time. In particular, we suggest that large artery stiffening likely progresses from proximal to distal large arteries and identification of the early onset of such changes (e.g., prior to marked changes in pulse wave velocity) may allow earlier diagnosis and thus more effective intervention, prior to the propagation of detrimental effects of large artery stiffening to distal muscular arteries and eventually the microvessels, changes to which may be more difficult to reverse pharmacologically. Hence, we seek to deepen our fundamental understanding of the basis of arterial stiffening and to enable better clinical assessments and treatment planning based on readily available data. Specifically, we hypothesize that central arteries stiffen due, in large part, to a cyclic-strain induced damage to or degradation of elastic fibers that likely progresses over time from proximal to distal arteries because of initial spatial distributions of elastin and associated wall strains. To test this hypothesis, we will quantify and compare for the first time progressive changes in wall mechanics, composition, and hemodynamics in 3 basic mouse models (wild-type, fibrillin-1 deficient, and fibulin-5 null), each subjected to 3 pharmacological inter- ventions (L-NAME, doxycycline, and BAPN). That is, we will use genetically modified mouse models of graded decreases in elastic fiber integrity, not initially diminished elastin, for this will allow progressive changes to be quantified independent of possible compensatory adaptations that occur during development in elastin deficient mice. We expect loss of nitric oxide (L-NAME group) to highlight a role of smooth muscle tone and exacerbate the progression of wall stiffening, diminished proteinase activity (doxycycline) to separate roles of mechanical damage and chemical degradation of elastin while attenuating wall stiffening, and inhibiting collagen cross-linking (BAPN) to separate the coupled effects of elastin on the stiffness of extant collagen from the role of new collagen deposition. The experimental data will be used to construct, verify, and validate a novel fluid-solid-interaction model that can reveal precisely the effects of individual determinants of wall stiffening on system-level hemodynamics. Once accomplished for the mouse, parametric studies will be performed on 3 prototypical models of hemodynamics in humans (young, middle-aged, and old) to reveal, for the first time, the effects of progressive wall stiffening on clinical metrics of hemodynamics such as pulse wave velocity, pulse pressure, and pulse pressure waveform. We submit that modeling studies alone can delineate effects of spatially and temporally progressive increases in arterial stiffening on system-level hemodynamics, with the potential to identify improved indicators of early stiffening that may allow an earlier clinical intervention that can prevent the longer-term irreversible changes to the microstructure that otherwise inevitably occur.    ","ACTIVITY":"R01","ADMINISTERING_IC":"HL","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"12/31/2013","BUDGET_START":"01/01/2014","BUDGET_END":"12/31/2015","CFDA_CODE":"837","CORE_PROJECT_NUM":"R01HL105297","ED_INST_TYPE":"BIOMED ENGR/COL ENGR/ENGR STA","FOA_NUMBER":"RFA-HL-10-027","FULL_PROJECT_NUM":"5R01HL105297-04","FUNDING_ICs":"NHLBI:386146\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL HEART, LUNG, AND BLOOD INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"NEW HAVEN","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"ENGINEERING (ALL TYPES)","ORG_DISTRICT":"03","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"YALE UNIVERSITY","ORG_STATE":"CT","ORG_ZIPCODE":"065103209","PHR":"PUBLIC HEALTH RELEVANCE: Cardiovascular disease remains the leading cause of death and disability in the USA and stiffening of central arteries is now an unquestioned independent risk factor for many such diseases, including heart attack, stroke, and end-stage renal disease. The six primary contributors to arterial stiffness are elastic fiber integrity, collagen organization, smooth muscle contractility, wall thickness, axial prestretch, and perivascular support, each of which has a molecular and cellular basis. We will be the first to combine genetically modified mouse models, pharmacological interventions, and sophisticated computational biomechanical models to delineate effects of these six contributors on arterial stiffness and hemodynamics. Our novel data will provide unique insights into mechanisms of arterial stiffening and our new fluid-solid-interaction model will increase our ability to interpret current clinical indicators of cardiovascular risk and identify new metrics that yield more information.","PI_IDS":"11309245;1950356 (contact);","PI_NAMEs":"FIGUEROA, CARLOS ALBERTO;HUMPHREY, JAY D. (contact);","PROGRAM_OFFICER_NAME":"OH, YOUNGSUK ","PROJECT_START":"09/30/2010","PROJECT_END":"12/31/2015","PROJECT_TERMS":"Abdomen;Affect;Aging;Ally;Animals;Aorta;arterial stiffness;Arteries;Attenuated;base;Biochemical;Biological;Biomechanics;Blood Vessels;Brain;Cardiovascular Diseases;Cardiovascular Physiology;cardiovascular risk factor;Cause of Death;Central Artery;Chemicals;Clinical;Clinical assessments;Clinical Treatment;Collagen;Collagen Fiber;Complex;computerized tools;Coupled;crosslink;Data;Deposition;Development;Dilatation - action;disability;Disease;Disease susceptibility;Dissection;Distal;Doxycycline;Early Diagnosis;early onset;effective intervention;Elastic Fiber;Elastin;End stage renal failure;endothelial dysfunction;Endothelium;Equation;Exhibits;Fatigue;FBN1;Fibrillar Collagen;fibulin;Functional disorder;Gene Mutation;Genetic;genome wide association study;Geometry;Growth;Heart;hemodynamics;Human;Hypertension;improved;indexing;Individual;inhibitor/antagonist;insight;Intervention;Kidney;Knockout Mice;Liquid substance;Longitudinal Studies;Matrix Metalloproteinase Inhibitor;Matrix Metalloproteinases;Measurable;Measures;Mechanics;Methods;Metric;Microfibrils;middle age;Modeling;Molecular;Motion;mouse model;Mus;Muscle;Muscle Tonus;Myocardial Infarction;NG-Nitroarginine Methyl Ester;Nitric Oxide;novel;Organ;Pathology;Peptide Hydrolases;Physiologic pulse;Play;pressure;prevent;Property;Protein-Lysine 6-Oxidase;public health relevance;Pulse Pressure;Resistance;Risk Assessment;Risk Factors;Role;Rupture;simulation;Smooth muscle (tissue);Solid;Spatial Distribution;Stretching;stroke;Structure;Study models;System;Testing;Thick;Time;tool;treatment planning;Validation;Work","PROJECT_TITLE":"Mechanisms Underlying the Progression of Arterial Stiffness in Hypertension","SERIAL_NUMBER":"105297","STUDY_SECTION":"ZHL1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"4","TOTAL_COST":"386146","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8643218","ABSTRACT_TEXT":"   DESCRIPTION (provided by applicant): The goal of this project is to discover genes underlying taste preferences, particularly those responsible for the preferences for sodium, calcium, and acids. Over the last 15 yr, several fundamental insights into the genetic and molecular basis of taste transduction have been made using mouse models but there are disadvantages to using mice, and many questions remain. The rat has the potential to be a better model. It has traditionally been used for taste preference experiments, and there is a massive literature dealing with rat physiology, nutrition and learning mechanisms. The problem has been that until recently genetic tools for studying the rat have not been available, but this has changed. This project will take advantage of a new consomic rat resource to investigate the genetic basis of taste preferences in rats. Preliminary work has identified consomic rat strains that differ from their background strain in preferences for sodium, calcium and acids. To exploit this, we now propose to better characterize the phenotype of the consomic rat strains, and isolate the genes involved by breeding congenic rat lines. The expression patterns of genes in the congenic interval will be surveyed to evaluate their potential contribution to the phenotype. These studies will lead to the discovery and characterization of genes responsible for taste preferences.      ","ACTIVITY":"R01","ADMINISTERING_IC":"DC","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"03/11/2014","BUDGET_START":"04/01/2014","BUDGET_END":"03/31/2015","CFDA_CODE":"173","CORE_PROJECT_NUM":"R01DC010149","ED_INST_TYPE":"","FOA_NUMBER":"PA-07-070","FULL_PROJECT_NUM":"5R01DC010149-05","FUNDING_ICs":"NIDCD:299648\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS","NIH_SPENDING_CATS":"","ORG_CITY":"PHILADELPHIA","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"02","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"MONELL CHEMICAL SENSES CENTER","ORG_STATE":"PA","ORG_ZIPCODE":"191043308","PHR":"PUBLIC HEALTH RELEVANCE: This project investigates the genetic controls of taste preferences. The goal is to find the genes that determine what we eat. Understanding the basic mechanisms underlying why we choose to consume particular foods and drinks is important for guiding nutritional interventions and policy. An understanding of how food choices are made will lead to the development of effective strategies and treatments to increase the intake of needed nutrients and decrease the intake of unneeded ones. Better food choices would reduce the incidence of many chronic diseases, including obesity, hypertension and osteoporosis.         ","PI_IDS":"1858728;","PI_NAMEs":"TORDOFF, MICHAEL G;","PROGRAM_OFFICER_NAME":"SULLIVAN, SUSAN L.","PROJECT_START":"04/01/2010","PROJECT_END":"03/31/2015","PROJECT_TERMS":"Acids;base;Bioinformatics;Breeding;Calcium;Candidate Disease Gene;Chromosomes;Chromosomes, Human, Pair 15;Chromosomes, Human, Pair 3;Chromosomes, Human, Pair 7;Chronic Disease;Citric Acid;congenic;congenic breeding;consomic;Data;Development;Dietary Intervention;Disadvantaged;drinking;Eating;Electrophysiology (science);Food;gene discovery;Gene Expression;Gene Expression Profile;Genes;Genetic;Goals;Health;Human;Human Genome;Hypertension;Incidence;insight;Intake;Knock-out;Lead;Learning;Literature;Measures;Metabolism;Modeling;Molecular Genetics;mouse model;Mouse Strains;Mus;Nutrient;nutrition;Obesity;Osteoporosis;Phenotype;Physiology;Policies;preference;public health relevance;Quantitative Trait Loci;rat genome;Rat Strains;Rattus;research study;Resources;Sodium;Solutions;Surveys;Taste Perception;Testing;Time;Tissue-Specific Gene Expression;tool;Transgenic Organisms;treatment strategy;Water;Work","PROJECT_TITLE":"Genetics of taste preferences","SERIAL_NUMBER":"10149","STUDY_SECTION":"SCS","STUDY_SECTION_NAME":"Somatosensory and Chemosensory Systems Study Section","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"5","TOTAL_COST":"299648","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8664454","ABSTRACT_TEXT":"   DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a common neurodegenerative disease where the causes of the disease are unknown for ~90% of cases. However, a variety of genetic mutations cause PD in ~10% cases. Among the genetic causes of PD, autosomal dominant forms of familial PD (FPD) share many of the pathological and clinical features with more common late onset sporadic PD. Recently, mutations in LRRK2 gene were shown to cause late-onset FPD with variable penetrance and a-synuclein (a-Syn) pathology (a-synucleinopathy). Thus, PD caused by LRRK2 may involve interactions with environmental and genetic factors. To understand the pathogenic involvement of LRRK2 in causing PD with a-synucleinopathy, we have generated conditional human LRRK2 (hLRRK2) transgenic (Tg) mouse model where high-levels of mutant (R1441C and G2019S) and wild type (WT) hLRRK2 expression can be achieved in subcortical regions. We will determine that when expressed in subcortical neurons, mutant hLRRK2 causes progressive neuropathology in mice, including the loss of dopaminergic neurons. Because only ~50% of mutant hLRRK2 carriers develop PD within 70 years of age, mutant hLRRK2 may combine with other factors to fully express the pathogenic potential. We will test this hypothesis by testing whether mutant hLRRK2 increases vulnerability in dopaminergic neurons to dopaminergic toxin. Further, we will determine whether there is a pathologic interaction between mutant hLRRK2 and a-Syn in causing neurodegeneration of PD relevant neuronal populations.        ","ACTIVITY":"R01","ADMINISTERING_IC":"NS","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"05/23/2014","BUDGET_START":"06/01/2014","BUDGET_END":"05/31/2015","CFDA_CODE":"853","CORE_PROJECT_NUM":"R01NS076160","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"PA-10-067","FULL_PROJECT_NUM":"5R01NS076160-04","FUNDING_ICs":"NINDS:307630\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE","NIH_SPENDING_CATS":"","ORG_CITY":"MINNEAPOLIS","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"NEUROSCIENCES","ORG_DISTRICT":"05","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF MINNESOTA","ORG_STATE":"MN","ORG_ZIPCODE":"554552070","PHR":" Mutations in LRRK2 are the most common genetic cause of late onset PD and resemble sporadic PD. By producing and studying transgenic mouse model with LRRK2-dependent neurodegeneration, we hope to gain new insights about the pathogenesis of PD. Such information will lead to novel therapeutic targets for PD.             ","PI_IDS":"6232922;","PI_NAMEs":"LEE, MICHAEL K;","PROGRAM_OFFICER_NAME":"SIEBER, BETH-ANNE ","PROJECT_START":"07/15/2011","PROJECT_END":"05/31/2016","PROJECT_TERMS":"Acute;Affect;Age;age related;Age-Years;Aging;alpha synuclein;Attenuated;Chronic;Clinical;Disease;dopaminergic neuron;gene environment interaction;Gene Mutation;Genetic;Human;Inherited;insight;Knock-in Mouse;Lead;Link;LRRK2 gene;Modeling;mouse model;Mus;mutant;Mutation;Nerve Degeneration;Neurodegenerative Disorders;neuron loss;Neurons;neuropathology;Neurotoxins;new therapeutic target;overexpression;Parkinson Disease;Pathogenesis;Pathologic;Pathology;Penetrance;Population;progressive neurodegeneration;Prosencephalon;Proteins;Role;Secondary to;Severities;synuclein;synucleinopathy;Testing;Therapeutic;Toxic effect;Toxin;Transgenic Mice;Transgenic Model;Viral","PROJECT_TITLE":"Neurodegenerative interactions in conditional LRRK2 Tg models","SERIAL_NUMBER":"76160","STUDY_SECTION":"NOMD","STUDY_SECTION_NAME":"Neural Oxidative Metabolism and Death Study Section","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"4","TOTAL_COST":"307630","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8751190","ABSTRACT_TEXT":"The Protein Core in the University of Kentucky Center for Molecular Medicine works with biomedical  investigators to facilitate the expression, purification, and characterization of recombinant proteins and other  macromolecules. It makes available equipment, instrumentation, and expertise not normally be found within  individual research laboratories. The Core has fermentors, bioreactors, and tissue culture facilities for  expressing recombinant protein in bacteria, yeast, insect, or mammalian cells as required. It also maintains  cell cracking equipment and an extensive facility for the purification of recombinant proteins. In addition, a  range of analytical instruments for biophysical characterization are available in the Core, including dynamic  light scattering, spectropolarimetry, fluorescence, isothermal titration calorimetry, high performance liquid  chromatography, analytical ultracentrifugation, and X-ray crystallography. Crystallography facilities include  instruments for automated crystallization trials, in house data collection equipment, and membership in a  group (SER-CAT) operating a state-of-the-art data collection facility at the Advanced Photon Source located  within Argonne National Laboratory. A Core staff member maintains the equipment, provides training and,  works with researchers on their individual projects. Experienced users have direct access to Core facilities,  while new users are first trained by Core personnel and assisted in initial experiments. Users with more  difficult projects receive additional assistance from the Core personnel. Service projects are undertaken  selectively for users who lack the expertise or personnel to carry out the work on their own. The Core is  used by investigators representing 50-70 research groups each year, with over 4200 individual uses of  instruments or facilities documented for the first four years of Phase II COBRE funding. Outreach activities  include the Core web site, talks given by Core associated faculty, individual and group training sessions, a  monthly research talk series, and participation in graduate courses and an NSF REU summer program. The  Core is active in obtaining new instrumentation and introducing new techniques. Transition to a selfsustaining  regional facility is planned over the course of Phase III COBRE funding.","ACTIVITY":"P30","ADMINISTERING_IC":"GM","APPLICATION_TYPE":"1","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"06/27/2014","BUDGET_START":"07/01/2014","BUDGET_END":"04/30/2015","CFDA_CODE":"","CORE_PROJECT_NUM":"P30GM110787","ED_INST_TYPE":"","FOA_NUMBER":"PAR-13-238","FULL_PROJECT_NUM":"1P30GM110787-01","FUNDING_ICs":"NIGMS:188051\\","FUNDING_MECHANISM":"Research Centers","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES","NIH_SPENDING_CATS":"","ORG_CITY":"LEXINGTON","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"06","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF KENTUCKY","ORG_STATE":"KY","ORG_ZIPCODE":"405060057","PHR":"This Protein Core in the Center for Molecular Medicine provides a variety of services aimed at the production  and characterization of proteins for investigator inflated biomedical research. The Core makes available well  maintained instruments and facilities not generally found in individual research labs, and provides both  training in their use and expert guidence. In addition, service projects carried out by Core personnel are  undertaken.","PI_IDS":"7875214;","PI_NAMEs":"RODGERS, DAVID W;","PROGRAM_OFFICER_NAME":"","PROJECT_START":"","PROJECT_END":"","PROJECT_TERMS":"analytical ultracentrifugation;Area;Bacteria;base;Behavior;Biological;Biomedical Research;biophysical properties;Bioreactors;Calorimetry;cell type;Cells;Centers of Research Excellence;Chromatography;Collaborations;Communities;Consult;Core Facility;Core Protein;Crystallization;Crystallography;Data Collection;design;Equipment;experience;Faculty;Fees;Fluorescence;Fostering;Funding;Goals;Grant;Growth;High Pressure Liquid Chromatography;Housing;Human Resources;Individual;Insecta;Institution;instrument;instrumentation;Kentucky;Laboratories;Laboratory Research;light scattering;macromolecule;Mammalian Cell;member;Mission;Molecular Medicine;operation;outreach;outreach program;Phase;Photons;Production;programs;Protein Chemistry;Proteins;Recombinant Proteins;Research;Research Personnel;research study;Resources;Schedule;Series;Services;Source;Structural Biologist;structural biology;Structure;Techniques;Time;tissue culture;Titrations;Training;Universities;web site;Work;X-Ray Crystallography;Yeasts","PROJECT_TITLE":"Protein Core","SERIAL_NUMBER":"110787","STUDY_SECTION":"ZGM1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"6091","SUFFIX":"","SUPPORT_YEAR":"1","TOTAL_COST":"","TOTAL_COST_SUB_PROJECT":"188051"}
{"APPLICATION_ID":"8669117","ABSTRACT_TEXT":"Despite significant advances in pig-to-primate organ xenotransplantation, long-term graft survival is currently limited by the development of a thrombotic microangiopathy and platelet sequestration in the grafted organ and/or a consumptive coagulopathy in the recipient. The present proposal tests homogeneous heparin sulfates (HSs) synthesized using computational modeling and enzymatic/chemical tools as outlined in Projects I (PL-I. Dr. Balagurunathan) and II (Pl-ll. Dr. Desai). We hypothesize that chemically-synthesized HSs designed to preferentially inhibit Factor Xa (FXa) and/or thrombin will ameliorate the thrombotic microangiopathy and/or consumptive coagulopathy seen in the context of pig-to-primate xenografts by inhibiting thrombin formation and platelet activation. In addition, HSs optimized to bind chemokines (from Project III) may act as chemokine decoy factors to prevent cell sequestration synergistically with anticoagulation. These HSs will be evaluated in the context of various xenotransplantation models using cells and organs from pigs genetically modified to protect against antibody/complement-mediated, inflammatory, and coagulation rejection mechanisms. These HS-based therapies will be tested by. - (i) in vitro assays to determine the best HS candidate drugs for further studies, (ii) ex vivo pig lung hemoperfusion using human blood, (iii) pig artery Tx in baboons, and (iv) pig kidney Tx in baboons. Model (ii) constitutes a short-duration model (with graft function measured in hours) allowing rapid screening of the HSs being tested, whereas models (iii) and (iv) constitute longer-duration models (days or weeks). Furthermore, the effect of the HS will be monitored (iii) in a low-antigen load model without immunosuppressive therapy, or (iv) in a high-antigen load model in which graft recipients will receive immunosuppressive therapy aimed at inhibiting the adaptive T cell response. The prime aim of the study is to identify one (or more) HS that is more specific and more efficient at inhibiting the development of thrombotic microangiopathy and consumptive coagulopathy than is the current clinically-used heparin, and that, furthermore, is not associated with the side-effects of heparin, e.g., bleeding, that limit the dosage that can be administered. The second aim is to investigate the synergy between the HS identified as being optimal with the genetic manipulations in the organ-source pig, e.g., expression of human thrombomodulin directed towards inhibiting thrombotic microangiopathy and consumptive coagulopathy. RELEVANCE (See instructions): The transplantation of organs from genetically-engineered pigs would provide an alternative source to human organs for clinical transplantation, but is currently complicated by coagulation disturbances that can be fatal. The administration of specific synthetic heparan sulfates that will be designed and investigated in this proposal are likely to prevent these coagulation disturbances, thus enabling xenotransplantation to advance to clinical trials.","ACTIVITY":"P01","ADMINISTERING_IC":"HL","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"05/27/2014","BUDGET_START":"06/01/2014","BUDGET_END":"05/31/2015","CFDA_CODE":"","CORE_PROJECT_NUM":"P01HL107152","ED_INST_TYPE":"","FOA_NUMBER":"RFA-HL-10-026","FULL_PROJECT_NUM":"5P01HL107152-04","FUNDING_ICs":"NHLBI:344353\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL HEART, LUNG, AND BLOOD INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"RICHMOND","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"03","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"VIRGINIA COMMONWEALTH UNIVERSITY","ORG_STATE":"VA","ORG_ZIPCODE":"232980568","PHR":"","PI_IDS":"6517000;","PI_NAMEs":"COOPER, DAVID KC;","PROGRAM_OFFICER_NAME":"","PROJECT_START":"","PROJECT_END":"","PROJECT_TERMS":"Adhesions;Adhesives;Adverse effects;Antibodies;Anticoagulants;Anticoagulation;Antigens;Arteries;base;Binding (Molecular Function);Biological Assay;Biology;Blood;Blood Coagulation Disorders;Blood Coagulation Factor;Blood Platelets;Cells;Chemicals;Chemistry;chemokine;Chemotaxis;clinical application;Clinical Trials;Coagulation Process;Complement;Computer Simulation;cytokine;Data;Data Analyses;Defect;design;Development;dosage;drug candidate;Face;Factor Xa;Family suidae;Genes;Genetic;Genetic Engineering;genetic manipulation;Glycosaminoglycans;graft function;Graft Survival;Hemoperfusion;Hemorrhage;Heparin;Heparitin Sulfate;Hour;Human;immunosuppressed;In Vitro;in vitro Assay;in vivo;Inflammation;Inflammatory;inhibitor/antagonist;Injury;Inorganic Sulfates;Instruction;Intervention;Kidney;Leukocytes;Lung;Measures;Mediating;Modeling;Modification;Molecular;Molecular Target;Monitor;monocyte;neutrophil;novel therapeutics;Organ;Organ Transplantation;Papio;Pathway interactions;Plasma;Platelet Activating Factor;Platelet Activation;Play;prevent;Primates;Production;prothrombinase complex;Relative (related person);research study;Role;screening;Site-Directed Mutagenesis;Source;T cell response;T-Lymphocyte;Technology;Testing;Therapeutic;Therapeutic immunosuppression;Thrombin;Thrombomodulin;tool;Transplantation;Unspecified or Sulfate Ion Sulfates;vascular inflammation;Xenograft procedure","PROJECT_TITLE":"Therapeutic assessment of synthetic heparin sulfates in transplantation models","SERIAL_NUMBER":"107152","STUDY_SECTION":"ZHL1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"6991","SUFFIX":"","SUPPORT_YEAR":"4","TOTAL_COST":"","TOTAL_COST_SUB_PROJECT":"344353"}
{"APPLICATION_ID":"8689019","ABSTRACT_TEXT":"The developmental origins hypothesis relates early exposures to endocrine disrupting chemicals (EDCs) to  the development of chronic diseases, including metabolic syndrome, a condition affecting up to 25% of US  adults and 30% of obese adolescents. Limited research in humans has considered the mechanisms by  which exposures to EDCs mixtures interact with diet to alter maternal and child metabolic homeostasis, nor  considered whether subsequent exposures during adolescence exacerbate risk of metabolic syndrome.  Pilot human and animal data from our Formative CEHC: 'Perinatal exposures, epigenetics, child obesity and  sexual maturation\" (P20 ESDI 8171/ RD834800, Pl: Peterson) suggest that the disruptive effects of  representative maternal EDCs on metabolic and epigenetic markers may differ across sensitive periods of  child development. Drawing on unparalleled institutional resources including the UM NIEHS Center of  Excellence Epigenetics Laboratory (P30 ES017885) and the Michigan Nutrition and Obesity Research  Center (MNORC, P30 DK089503), this project will test the hypothesis that EDC mixtures (BPA, phthalates,  lead, cadmium) via epigenetic mechanisms induce oxidative stress (tyrosine oxidation products), disrupt  metabolic homeostasis (free fatty acids, amino acids, Acyl-carnitine) and lead to changes in gene  transcription and metabolic function. We further hypothesize that dietary macro- and micronutrient intake  and dietary patterns during pregnancy and adolescence will modify the impact of EDC mixtures on these  outcomes. Study participants include the Michigan Mother-Infant Pairs (MMIP) cohort (n=80) (extension of  R01 ES017005, PI: Padmanabhan) and 400 children followed from pregnancy to 8-15 years of age through  our 18-yr Early Life Exposures in Mexico to ENvironmental Toxicants (ELEMENT) collaboration with  Mexico's Instituto Nacional de Salud Publica (INSP). Findings will: 1) provide proof of concept that EDC  mixtures perturb metabolic homeostasis, 2) clarify the role of diet in amplifying or negating such effects, 3)  illustrate the epigenetic and transcriptional changes involved and 4) inform the design of future interventions  to modify metabolic consequences of EDC exposures both in utero and during the pubertal transition.","ACTIVITY":"P01","ADMINISTERING_IC":"ES","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"06/23/2014","BUDGET_START":"06/01/2014","BUDGET_END":"05/31/2015","CFDA_CODE":"","CORE_PROJECT_NUM":"P01ES022844","ED_INST_TYPE":"","FOA_NUMBER":"RFA-ES-12-001","FULL_PROJECT_NUM":"5P01ES022844-02","FUNDING_ICs":"NIEHS:201583\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES","NIH_SPENDING_CATS":"","ORG_CITY":"ANN ARBOR","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"12","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF MICHIGAN","ORG_STATE":"MI","ORG_ZIPCODE":"481091274","PHR":"Metabolic syndrome affects ~25% of U.S. adults and up to 30% of obese adolescents. Understanding how  exposures to EDCs during pregnancy and adolescence may interact with diet to lead to metabolic  dysregulation is .highly relevant to clinical and public health practice. Results of this study will inform design  of interventions to reduce health effects of toxicant mixtures in children during key developmental periods.","PI_IDS":"1868686;2515822 (contact);","PI_NAMEs":"PADMANABHAN, VASANTHA;PETERSON, KAREN EILEEN (contact);","PROGRAM_OFFICER_NAME":"","PROJECT_START":"06/01/2014","PROJECT_END":"05/31/2018","PROJECT_TERMS":"15 year old;Adolescence;Adolescent;Adult;Affect;Age;Amino Acids;animal data;Antioxidants;Biological Markers;Blood;Cadmium;Candidate Disease Gene;Carnitine;Chemical Exposure;Chemicals;Child;Child Development;Chronic Disease;Clinical;cohort;Collaborations;design;Development;Diet;Dietary intake;Dietary Practices;disorder risk;DNA Methylation;early life exposure;Elderly;Endocrine Disruptors;epigenetic marker;Epigenetic Process;Exposure to;fetal;Fetal development of the mammalian embryo or fetus;Future;Genetic Transcription;Growth;Health;Homeostasis;Human;human data;in utero;Infant;Intake;Intervention;Laboratories;Lead;Life;Macronutrients Nutrition;Mediating;Metabolic;Metabolic Marker;Metabolic syndrome;Metabolism;Metals;Mexico;Michigan;Micronutrients;Minerals;Mothers;National Institute of Environmental Health Sciences;Nonesterified Fatty Acids;nutrition;Obesity;Outcome;oxidation;Oxidative Stress;Participant;Perinatal Exposure;peripubertal period;phthalates;Physiological Adaptation;Pregnancy;prenatal;Public Health Practice;ranpirnase;Research;Resources;Risk;Role;Sexual Maturation;Testing;therapy design;Toxic Environmental Substances;toxicant;Toxicant exposure;Tyrosine;Umbilical Cord Blood","PROJECT_TITLE":"Project 2:  Metabolic Consequences of In Utero and Peripubertal Toxicant-Diet E","SERIAL_NUMBER":"22844","STUDY_SECTION":"ZES1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"7856","SUFFIX":"","SUPPORT_YEAR":"2","TOTAL_COST":"","TOTAL_COST_SUB_PROJECT":"201583"}
{"APPLICATION_ID":"8640182","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant):     PROJECT SUMMARY/ABSTRACT  DNA EXCISION REPAIR AND DNA DAMAGE CHECKPOINTS  Nucleotide excision repair and DNA damage checkpoints are two major cellular responses to DNA damage that are essential for genomic stability. The goal of our research is to understand the molecular mechanisms of these systems and to use this information to develop cancer prevention and treatment strategies. To accomplish this goal we will perform the following experiments. Aim 1. Nucleotide Excision Repair and Skin Cancer Development as a Function of the Circadian Clock.  Our studies on the regulation of nucleotide excision repair in mammals have revealed that excision repair exhibits high amplitude oscillation with a daily periodicity in most mouse tissues. We will analyze the daily variability of excision repair of UV photoproducts in skin and determine whether this variability is associated with carcinogenicity of UV light delivered at different times of the day. The results of this study will enable us to make specific recommendations to lower the incidence of skin cancer induced by sunlight and other UV sources. Aim 2. Biochemical Analysis of the UV-Induced DNA Damage Checkpoint.  We will purify and characterize the proteins involved in ATR kinase-mediated DNA damage checkpoint response which is the primary checkpoint pathway activated by UV and UV-mimetic chemical agents. We will reconstitute this checkpoint system from highly purified components in vitro and analyze the coupling of nucleotide excision repair with the ATR checkpoint signaling pathway. Understanding this DNA damage signaling pathway should facilitate the design of novel chemotherapeutic approaches to treat cancer.        ","ACTIVITY":"R01","ADMINISTERING_IC":"GM","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"03/25/2014","BUDGET_START":"04/01/2014","BUDGET_END":"03/31/2015","CFDA_CODE":"859","CORE_PROJECT_NUM":"R01GM032833","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"PA-10-067","FULL_PROJECT_NUM":"5R01GM032833-31","FUNDING_ICs":"NIGMS:612652\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES","NIH_SPENDING_CATS":"","ORG_CITY":"CHAPEL HILL","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"BIOCHEMISTRY","ORG_DISTRICT":"04","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIV OF NORTH CAROLINA CHAPEL HILL","ORG_STATE":"NC","ORG_ZIPCODE":"275990001","PHR":"     PROJECT NARRATIVE  We propose to carry out experiments on two major cellular responses to UV- and UV-mimetic drug- induced DNA damage: Translational research on nucleotide excision repair in mice and mechanistic research on ATR-mediated DNA damage checkpoints. We will use biochemical, cell biological, genetic, and animal model systems in our research and provide mechanistic and animal model data for cancer prevention and treatment.            ","PI_IDS":"1898413;","PI_NAMEs":"SANCAR, AZIZ;","PROGRAM_OFFICER_NAME":"WILLIS, KRISTINE AMALEE","PROJECT_START":"12/01/1983","PROJECT_END":"03/31/2016","PROJECT_TERMS":"abstracting;Animal Model;base;Biochemical;biochemical model;Biochemical Pathway;Biochemistry;Biological Assay;Biological Models;Brain;cancer prevention;cancer therapy;carcinogenicity;Cell Cycle;Cells;Checkpoint kinase 1;Chemical Agents;chromatin immunoprecipitation;circadian pacemaker;Circadian Rhythms;Complex;coping;Coupling;Data;design;Development;DNA;DNA Damage;DNA damage checkpoint;Dose-Rate;Excision Repair;Exhibits;Exposure to;Funding;Genetic Models;Genome Stability;Genotoxic Stress;Goals;Grant;Human;In Vitro;in vivo;Incidence;Investigation;irradiation;Link;Liver;Malignant Neoplasms;Mammalian Cell;Mammals;Measures;Mediating;mimetics;Modeling;Molecular;Mus;novel;nuclease;Nucleotide Excision Repair;Pathway interactions;Periodicity;Pharmaceutical Preparations;Phosphotransferases;programs;Proteins;public health medicine (field);Recommendation;reconstitution;Regulation;repaired;Research;Research Infrastructure;Research Personnel;research study;Resolution;response;Scheme;Set protein;Signal Pathway;Signal Transduction;Skin;Skin Cancer;Source;Sunlight;sunlight-induced;System;Testing;Time;Tissues;transcription factor;Translational Research;treatment strategy;ultraviolet irradiation;Ultraviolet Rays;UV induced;UV induced DNA damage;vector;Work","PROJECT_TITLE":"DNA Excision Repair and DNA Damage Checkpoints","SERIAL_NUMBER":"32833","STUDY_SECTION":"MGA","STUDY_SECTION_NAME":"Molecular Genetics A Study Section","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"31","TOTAL_COST":"612652","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8600985","ABSTRACT_TEXT":" 7. PROJECT SUMMARY Myocardial infarction resulting from ischemic injury is a prominent and common feature of cardiovascular morbidity and mortality. Cardiac myosin binding protein-C (cMyBP-C) is, by its degradation during proteolysis, an important determinant of myocardial contractile pathogenesis during I-R injury. Briefly, cMyBP-C is a thick filament-associated protein that stabilizes myosin, an important component of the contractile machinery, to regulate sarcomeric structure and function in the heart. Mutations in the cMyBP-C gene account for ~34% of all cardiomyopathy cases, 70% of which are predicted to produce unstable truncated proteins. During I-R injury, we demonstrated that extensive fragmentation of cMyBP-C correlates with altered sarcomeric structure and contractile dysfunction. Therefore, while the short-term goal is to elucidate the proteolytic and pathogenic properties of cMyBP-C in the clinical context of cardioprotection during ischemia-reperfusion (I-R) injury, the long-term goal is to determine the mechanisms by which cMyBP-C stabilizes sarcomeric structure and function in order to confer cardioprotection during I-R injury. More specifically, our preliminary studies show that calpains degrade cMyBP-C into several fragments and that the 29-kDa fragment is the predominant fragment in vitro. Such proteolysis leads to the release of the 29-kDa fragment into the blood stream during I-R injury in mice. Moreover, mass spectrometry analyses confirm that the release of the 29-kDa fragment is associated with the calpain-targeted site (CTS), which is a conserved phosphorylation motif that possibly regulates its cleavage. From a therapeutic perspective, these findings indicate that the ablation of the CTS could result in resistance to calpain-mediated proteolysis, thus abrogating release of the 29-kDa fragment. Therefore, we propose that inhibition of CTS cleavage would secure the structural integrity of cMyBP-C, thus preserving contractile structure and function. However, the clinical and pathogenic significance of cMyBP-C degradation, as well as the properties of its proteolysis, have not been determined and therefore represent a clinically important area of translational research. The goal, therefore, is to determine the correlation between the release of the 29- kDa fragment in the blood and contractile dysfunction, demonstrate its toxic effects in cardiomyocytes and examine how the inhibition of CTS cleavage in cMyBP-C protects the heart from I-R injury. Overall, the proposed research aims to define the stability and function of cMyBP-C in the context of supportive therapy during I-R injury, in general, and heart muscle contractility, specifically. To achieve our goals, Specific Aim 1 will determine the levels of 29-kDa fragment in the blood, according to infarct size and contractile function during I-R injury. Specific Aim 2 will determine the pathogenic properties of the 29-kDa fragment in the context of myosin function. Specific Aim 3 will determine whether site-specific inhibition of the CTS, as defined above, can preserve cMyBP-C stability and function during I-R injury and thus confer cardioprotection. Importantly, once the kinetics of the 29-kDa fragment have validated that this peptide is quantifiable in the serum of wild-type non-transgenic mice with induced I-R injury, we can confirm its potential as a clinically useful readout of post-ischemic myocardial infarction. Our experimental approach is comprehensive, ranging from the analysis of molecular interactions to functional assessments of sarcomeric arrangement and function, both in vitro and in vivo. I-R injury will be induced in wild-type non-transgenic mice to define the sequential release of the 29-kDa fragment and its blood serum levels in relation to infarct size, calpain activities, and myocardial function, compared with controls. Adult mouse cardiomyocytes have been chosen as the model system to investigate the pathogenic properties of the 29-kDa fragment by using recombinant adenoviruses and peptides. To determine the association between the CTS in cMyBP-C and cardioprotection, we will use transgenic mice expressing cMyBP-C in which the CTS has been ablated and bred into the cMyBP-C null background, compared with transgenic mice expressing phospho-mimetic and wild-type cMyBP-C controls. Endpoint measurements include the amount of the 29-kDa fragment in the blood correlated with infarct area and cardiac function, calpain activity, cMyBP-C phosphorylation levels, intracellular Ca2+ transients, Mg2+-ATPase activity, myofilament Ca2+ sensitivity, molecular binding studies, sarcomere structure and function.","ACTIVITY":"R01","ADMINISTERING_IC":"HL","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"12/05/2013","BUDGET_START":"01/01/2014","BUDGET_END":"12/31/2015","CFDA_CODE":"837","CORE_PROJECT_NUM":"R01HL105826","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"PA-10-067","FULL_PROJECT_NUM":"5R01HL105826-04","FUNDING_ICs":"NHLBI:329648\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL HEART, LUNG, AND BLOOD INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"MAYWOOD","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"PHYSIOLOGY","ORG_DISTRICT":"","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"LOYOLA UNIVERSITY CHICAGO","ORG_STATE":"IL","ORG_ZIPCODE":"601533328","PHR":" 8. PROJECT NARRATIVE The long-term objective is to understand the functional consequences of cardiac myosin binding protein-C protein on heart function. Specifically, the proposed studies will examine the association between cardiac myosin binding protein-C degradation and cardiac dysfunction, leading to the development of potential cardioprotective therapeutic approaches by site-specific protein modification.","PI_IDS":"10267923;","PI_NAMEs":"SADAYAPPAN, SAKTHIVEL;","PROGRAM_OFFICER_NAME":"ADHIKARI, BISHOW B.","PROJECT_START":"01/01/2011","PROJECT_END":"12/31/2015","PROJECT_TERMS":"Ablation;Accounting;Actins;Adenoviruses;Adult;Amino Acid Sequence;Antibodies;Area;base;Binding (Molecular Function);Biological Markers;Biological Models;Blood;Blood specimen;Breeding;c-Myc Staining Method;Ca(2+) Mg(2+)-ATPase;Calpain;Cardiac;Cardiac Myocytes;Cardiac Myosins;Cardiomyopathies;Cardiomyopathy, Hypertrophic, Familial;Cardiovascular system;citrate carrier;Cleaved cell;Clinical;Complex;Custom;Cyclic AMP-Dependent Protein Kinases;Data;Development;Functional disorder;Generations;Genes;Goals;Heart;heart function;In Vitro;in vivo;Infarction;injured;Injury;Ischemia;Kinetics;Link;Mass Spectrum Analysis;Measurement;Mediating;Microfilaments;mimetics;Modification;Molecular;Morbidity - disease rate;Mortality Vital Statistics;Mus;Muscle;Mutation;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocardium;Myosin ATPase;myosin-binding protein C;novel;Organ;Pathogenesis;Peptides;Phosphorylation;Post-Translational Protein Processing;prevent;Property;Protein Dephosphorylation;Proteins;Proteolysis;Recombinants;Reperfusion Injury;Reperfusion Therapy;Research;Resistance;Role;Sarcomeres;Secure;Serum;Severities;Site;Stream;Structure;Supportive care;Testing;Therapeutic;Thick Filament;Thin Filament;Time;Toxic effect;Transgenic Mice;Translational Research;Western Blotting","PROJECT_TITLE":"Cardiac Myosin Binding Protein-C: Structure and Function","SERIAL_NUMBER":"105826","STUDY_SECTION":"CCHF","STUDY_SECTION_NAME":"Cardiac Contractility, Hypertrophy, and Failure Study Section","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"4","TOTAL_COST":"329648","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8626247","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): The capacity of the ventricles to perform work (i.e., power) is essential for moving blood throughout the circulatory system. Ventricular/myocyte power is determined ultimately by three myofibrillar properties;(i) the amount of force developed, (ii) the rate of force development, and (iii) the rate that myocardium shortens against loads. However, the sub-cellular processes that determine these properties are incompletely understood. The overall purpose of this study is to determine the sub-cellular factors that regulate myocyte power generating capacity. The specific objectives of the proposed studies are designed to determine (1) if PKA-mediated phosphorylation of cardiac troponin I (cTnI) is both necessary and sufficient to dictate sarcomere length dependence of force generation in cardiac myocytes, (2) how titin, MyBP-C, and myosin cross-bridges interact to modulate sarcomere length dependence of power output, and (3) to determine the time-course of changes in sarcomere length dependence of force, rates of force development, loaded shortening, and power output during the progression of heart failure. A rodent model of heart failure will be used to test the hypothesis that myocytes in compensated hearts exhibit greater sarcomere length dependence of force and power output due to a combination of greater expression of the larger N2BA titin isoform and greater PKA- induced myofibrillar protein phosphorylation, but with progression to ventricular failure sarcomere length dependence of force and power is markedly reduced due to reduced PKA- mediated phosphorylation of titin, MyBP-C, and cTnI. These studies are highly significant in their potential to determine the basis for the control of power-generating capacity in healthy myocytes and how these processes are altered with the progression of heart failure.        ","ACTIVITY":"R01","ADMINISTERING_IC":"HL","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"03/13/2014","BUDGET_START":"03/01/2014","BUDGET_END":"02/28/2015","CFDA_CODE":"837","CORE_PROJECT_NUM":"R01HL057852","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"PA-10-067","FULL_PROJECT_NUM":"5R01HL057852-16","FUNDING_ICs":"NHLBI:363289\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL HEART, LUNG, AND BLOOD INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"COLUMBIA","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"PHARMACOLOGY","ORG_DISTRICT":"04","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF MISSOURI-COLUMBIA","ORG_STATE":"MO","ORG_ZIPCODE":"652111230","PHR":" The goal of this project is to understand the factors that control the power generating capacity of individual cardiac myocytes. The control of myocyte power output dictates the pumping capacity of healthy hearts and dysregulation of these control factors contributes to pathological heart conditions, which afflict nearly 6 million citizens of th United States and is the most common cause of hospitalization of US citizens over 65 years of age.                        ","PI_IDS":"1912085;","PI_NAMEs":"MCDONALD, KERRY S;","PROGRAM_OFFICER_NAME":"ADHIKARI, BISHOW B.","PROJECT_START":"09/01/1997","PROJECT_END":"02/28/2016","PROJECT_TERMS":"Address;Age-Years;Attenuated;base;Binding (Molecular Function);Biochemical;Blood;Cardiac;Cardiac Myocytes;Cardiovascular system;Cell physiology;Characteristics;connectin;Contracts;Cyclic AMP-Dependent Protein Kinases;Dependence;Development;Exhibits;extracellular;Failure (biologic function);flexibility;Generations;Goals;Heart;Heart failure;Hospitalization;Individual;Laboratories;Length;Measurement;Mechanics;Mediating;Microfilaments;Molecular;Movement;Muscle Cells;Myocardial;Myocardium;Myosin ATPase;Myosin Heavy Chains;myosin-binding protein C;novel;Output;Phosphorylation;Physiological;Population;Preparation;Process;Production;Property;Protein Isoforms;Proteins;Pump;Radial;Records;Regulation;Research Design;research study;Rodent Model;Role;Sarcomeres;Speed (motion);Structure;Techniques;Testing;Thin Filament;Time;titin 2;tool;Transgenic Animals;Transgenic Organisms;Troponin I;United States;Ventricular;Work","PROJECT_TITLE":"Regulation of Work Capacity in Cardiac Myocytes","SERIAL_NUMBER":"57852","STUDY_SECTION":"ZRG1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"16","TOTAL_COST":"363289","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8620654","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant):  In cancer patients, determination of whether a malignancy has spread is the single most important factor used to develop a therapeutic plan and to predict prognosis. In most cases, cancer cells initially spread through regional lymph nodes. Therefore, clinical evaluation for the presence of regional lymph node metastases is of paramount importance. Unfortunately, there are no real-time, non-invasive clinical methods that can reliably detect and diagnose micrometastases in lymph nodes. Therefore, there is an urgent clinical need for an imaging technique that is widely available, is non-invasive and simple to perform, is safe, and can reliably detect and adequately diagnose lymph node micrometastases in real time.  The overall goal of our research program is to develop an advanced, in-vivo, noninvasive, molecular specific imaging technology, i.e., integrated ultrasound and photoacoustic imaging combined with targeted plasmonic nanosensors, capable of immediate and accurate assessment of sentinel lymph node micrometastases in real time. The underlying hypothesis of this project is that photoacoustic imaging integrated with widely used clinical ultrasound imaging is possible and both ultrasound and photoacoustic imaging can be performed in real time, yielding an immediate diagnosis and allowing early implementation of treatment.  A wide range of scientific and engineering, biomedical and clinical problems must be addressed to fully explore the capabilities of molecular specific ultrasound and photoacoustic lymphatic (MS-USPAL) imaging in detection and characterization of sentinel lymph node micrometastases. The current application is focused on important aspects of clinical translation of MS-USPAL imaging. We will develop and validate clinically translatable plasmonic nanosensors for MS-USPAL. We will use ultra-small gold nanoparticles to target epidermal growth factor receptor (EGFR), which is overexpressed in squamous carcinoma and in many other epithelial neoplasms. For highly sensitive detection of cancer cells, we will explore EGF receptor mediated endocytosis and the effect of plasmon resonance coupling between closely spaced molecular specific nanoparticles. The ultra-small size of nanoparticles will be highly favorable for rapid clearance from the body which will allow safe transition into clinical practice Additionally, 5 nm ligand capped gold nanoparticles will greatly reduce nonspecific interactions and reduce the uptake of nanoparticles by immune cells such as macrophages present due to lymph node inflammation, thus diminishing false positive results. Furthermore, we will design and construct a prototype of the clinical MS-USPAL imaging system capable of imaging 5 nm nanoparticles in-vivo.         ","ACTIVITY":"R01","ADMINISTERING_IC":"EB","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"02/20/2014","BUDGET_START":"03/01/2014","BUDGET_END":"02/28/2015","CFDA_CODE":"286","CORE_PROJECT_NUM":"R01EB008101","ED_INST_TYPE":"BIOMED ENGR/COL ENGR/ENGR STA","FOA_NUMBER":"PA-10-067","FULL_PROJECT_NUM":"5R01EB008101-07","FUNDING_ICs":"NIBIB:551942\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING","NIH_SPENDING_CATS":"","ORG_CITY":"AUSTIN","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"BIOMEDICAL ENGINEERING","ORG_DISTRICT":"25","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF TEXAS, AUSTIN","ORG_STATE":"TX","ORG_ZIPCODE":"787121532","PHR":"  In cancer patients, the determination of the spread of malignancy is the single most important factor to develop a therapeutic plan and predict prognosis. In most cases, cancer cells initially spread through regional lymph nodes. Thus, a technology such as molecular specific ultrasound and photoacoustic lymphatic imaging, capable of in-vivo, noninvasive and accurate assessment of regional metastases in real time, can simplify and improve management of patients with epithelial malignancies, significantly improve public health, and reduce medical costs.            ","PI_IDS":"7085501 (contact);6647553;","PI_NAMEs":"EMELIANOV, STANISLAV Y (contact);SOKOLOV, KONSTANTIN V;","PROGRAM_OFFICER_NAME":"LIU, CHRISTINA ","PROJECT_START":"09/01/2007","PROJECT_END":"02/29/2016","PROJECT_TERMS":"acoustic imaging;Address;Algorithms;Animal Model;Animals;Antibodies;antigen binding;Binding (Molecular Function);Binding Sites;Biodistribution;Biological;biomaterial compatibility;Biomedical Engineering;cancer cell;Cancer Patient;Cancerous;Cell Culture Techniques;Cells;Clinical;clinical practice;cost;Coupling;cytotoxicity;design and construction;Detection;Diagnosis;Diagnostic Imaging;Disseminated Malignant Neoplasm;Epidermal Growth Factor Receptor;Epithelial;Epithelial Cells;Epithelial Neoplasms;Feces;Funding;Goals;Gold;Head and neck structure;Human;Image;Image Analysis;image processing;Imaging Techniques;Imaging technology;Immune;improved;in vivo;Inflammation;Injection of therapeutic agent;intraoperative imaging;Intravenous;Lasers;Left;Life;Ligands;lymph nodes;Lymphatic;Lymphatic System;Lymphocyte;macrophage;Malignant Neoplasms;Maps;Medical;Methods;Micrometastasis;Molecular;molecular/cellular imaging;Monitor;mouse model;Mus;nanoparticle;nanosensors;Neoplasm Metastasis;Optics;Organ;outcome forecast;overexpression;Pathway interactions;Patients;photoacoustic imaging;Physiologic pulse;plasmonics;Primary Neoplasm;programs;Property;prototype;public health medicine (field);receptor mediated endocytosis;Research;research clinical testing;Resected;Resolution;Sampling;Screening for cancer;Sensitivity and Specificity;Sentinel Lymph Node;Signal Transduction;Slide;Source;Specificity;Specimen;Squamous cell carcinoma;System;Techniques;Technology;Testing;Therapeutic;Time;Tissue Sample;Tissues;Toxic effect;Translations;Ultrasonic Transducer;Ultrasonography;uptake;Urine;Xenograft procedure","PROJECT_TITLE":"Acoustic Imaging of Sentinel Node Matastasis using Plasmonic Nanosensors","SERIAL_NUMBER":"8101","STUDY_SECTION":"MEDI","STUDY_SECTION_NAME":"Medical Imaging Study Section","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"7","TOTAL_COST":"551942","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8646949","ABSTRACT_TEXT":"   DESCRIPTION (provided by applicant): The selectins are adhesion molecules belonging to the C-type lectin family. They are expressed constitutively on the surface of blood leukocytes and on activated endothelial cells and platelets. The selectins prominently bind O-linked glycans that are bound to Ser/Thr residues on a variety of glycoprotein scaffolds. Such binding between selectins and O-glycans initiate a series of steps that eventually results in the adhesion of leukocytes to blood vessel walls at sites of inflammation. This biomolecular interaction also conditions normal immune response, and it plays an important role in certain types of cardiovascular disorders and cancer metastatic processes. It is widely believed that controlling the rate of leukocyte adhesion by antagonizing selectin-ligand interactions can lead to new therapies to combat a variety of vascular ailments. Thus, in this proposal, we develop metabolic strategies to control leukocyte-endothelial interactions by engineering the glycans that are expressed on natural selectin-ligands. The specific aims are: Aim 1: To evaluate the feasibility of using monosaccharide analogs to alter glycan structures and leukocyte cell adhesion properties. Here, we test the possibility that analogs of the naturally occurring monosaccharide, GalNAc and also Fucose, can be fed to cells in order to modify either the core or terminal structures of glycans that function as the natural ligands for the selectins. We evaluate the ability and mechanism by which these chemical inhibitors permeate cells, engage and modify glycan biosynthetic pathways, and inhibit cell adhesion. Aim 2: To define the precise 1(2,3) sialyltransferase(s) regulating leukocyte adhesion to L-, E- and P-selectin in humans. Here, we either over- express specific sialyltransferases belonging to the ST3Gal family in leukocytes, or stably silence one or more ST3Gals at the same time in these cells. The effect of this \"system perturbation\" on selectin-ligand glycan structure and leukocyte cell adhesion function under fluid shear is evaluated. Aim 3: To determine the role for reversible sialylation in regulating leukocyte selectin-ligand structure. Here, we quantify the extent to which human ST3Gals catalyze readily reversible reactions, a property called 'reversible sialylation'. We then evaluate if 'reversible sialylation'plays an important role during the biosynthesis of selectin-ligands. Success in this aim will demonstrate that besides enzymatic rate constants that drive glycoconjugate synthesis in living cells, equilibrium processes governed by reversible enzymatic activity may also control glycan biosynthesis. Diverse experimental methods are applied to accomplish the above aims. These include cell adhesion studies under controlled flow conditions, in vivo experiments in a mouse model of inflammation, and lentiviral strategies to silence or overexpress specific genes in human leukocytes and hematopoietic progenitor/stem cells. In the long run, we anticipate that novel strategies to antagonize selectin-ligand binding interactions will be identified from this work that may aid future drug design.      ","ACTIVITY":"R01","ADMINISTERING_IC":"HL","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"03/21/2014","BUDGET_START":"04/01/2014","BUDGET_END":"03/31/2015","CFDA_CODE":"837","CORE_PROJECT_NUM":"R01HL063014","ED_INST_TYPE":"BIOMED ENGR/COL ENGR/ENGR STA","FOA_NUMBER":"PA-10-067","FULL_PROJECT_NUM":"5R01HL063014-13","FUNDING_ICs":"NHLBI:265749\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL HEART, LUNG, AND BLOOD INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"BUFFALO","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"ENGINEERING (ALL TYPES)","ORG_DISTRICT":"26","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"STATE UNIVERSITY OF NEW YORK AT BUFFALO","ORG_STATE":"NY","ORG_ZIPCODE":"142600001","PHR":" This proposal lies at the interface of bioengineering, biochemistry and medicine. It studies protein-carbohydrate binding interactions that regulate the adhesion of blood leukocytes (white blood cells) to endothelial cells that line blood vessel walls. The goal is to develop novel glycan/carbohydrate engineering approaches to modulate this cell adhesion event, since this can lead to new strategies to ameliorate inflammatory ailments.         ","PI_IDS":"3128242;","PI_NAMEs":"NEELAMEGHAM, SRIRAM;","PROGRAM_OFFICER_NAME":"SARKAR, RITA ","PROJECT_START":"04/01/2001","PROJECT_END":"03/31/2015","PROJECT_TERMS":"Address;Adhesions;Anabolism;analog;base;beta-galactoside alpha-2,3-sialyltransferase;Binding (Molecular Function);Biochemistry;Biomedical Engineering;Blood;Blood Platelets;Blood Vessels;Buffers;C-Type Lectins;carbohydrate receptor;carbohydrate structure;Carbohydrates;Cardiovascular Diseases;Cell Adhesion;Cell Adhesion Molecules;Cell Line;Cell Surface Receptors;Cells;Chemicals;combat;Data;Disease;Drug Design;Drug Kinetics;Endothelial Cells;Engineering;enzyme activity;Enzymes;Equilibrium;Event;Exhibits;Family;Family member;feeding;Fucose;Future;Galactose;Gene Expression;Genes;Glycoconjugates;Glycolipids;Glycoproteins;Glycosaminoglycans;glycosylation;glycosyltransferase;Goals;Golgi Apparatus;Half-Life;Hematopoietic;Human;Immune response;in vivo;Indium;Infiltration;Inflammation;Inflammatory;inhibitor/antagonist;insight;interest;knock-down;Lead;Leukocytes;Life;Ligand Binding;Ligands;Link;Liquid substance;Malignant Neoplasms;Mediating;Medicine;Membrane Glycoproteins;Metabolic;metastatic process;Methods;migration;MMP11 gene;Monosaccharides;mouse model;Mus;novel;novel strategies;Organ;overexpression;P-Selectin;P-selectin ligand protein;Pathology;Pathway interactions;Pharmacodynamics;Physiological;Plasma;Play;Polysaccharides;premature;prevent;Process;progenitor;Property;Proteins;Reaction;Reporting;research study;RNA Interference;Role;scaffold;Selectins;Series;Serum;sialylation;Sialyltransferases;Site;small molecule;ST3Gal II;ST3Gal IV;stem;Stem cells;Structure;Subfamily lentivirinae;success;Surface;System;Testing;Time;Tissues;tool;Trisaccharides;Ursidae Family;Vascular Endothelial Cell;Work","PROJECT_TITLE":"Selectin mediated cell adhesion under hydrodynamic shear","SERIAL_NUMBER":"63014","STUDY_SECTION":"ZRG1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"13","TOTAL_COST":"265749","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8685872","ABSTRACT_TEXT":"   DESCRIPTION (provided by applicant): A number of bacterial natural products contain substituted ???-unsaturated-?-lactones. The chemical nature of the substituents alters the biological activity considerably. For natural products such as fostriecin and phoslactomycins (PLMs), the ?-substituent is a linear polyketide chain and unusual in that it has multiple cis double bonds and a phosphate group. The PLMs exhibit remarkably selectivity and potent activity against human fungal pathogens, including Aspergillus fumigatus. The DNA encoding the PLM and fostriecin biosynthetic processes have been cloned, sequenced and analyzed. It has been shown that both natural products are generated by modular polyketide synthases (PKSs). In the case of PLM much of the biosynthetic process has been deciphered. The knowledge and genetic tools provided through ongoing PLM biosynthetic studies has allowed the generation of blocked mutants, hybrid pathways, and mutasynthetic approaches to access new natural products based around the PLM skeleton. These compounds are generally obtained in excellent fermentation yield (10-50 mg/L) from fermentations and include significant structural diversity both around the lactone core and in the delta substituent. Additional structural variation has been obtained by chemical and efficient enzymatic modification of these new PLM core structures. The proposal has 4 aims. Aim 1 will test a hypothesis for how modules in both systems establish the unusual cis double bonds in the ?-substituent. Aim 2-3 will test a hypothesis that the cis double bond of the unsaturated lactone, is not established by a canonical dehydration domain within a PKS module, but rather an unprecedented decarboxylative elimination from a malonylated pathway intermediate. A series of chemical, biochemical, genetic and structural approaches will investigate the enzyme-catalyzed elimination reaction, determine how the malonylated intermediate is generated, and the sequence of these steps in the PLM biosynthetic pathway. Aims 4 will focus on evaluating the antifungal activity of new PLMs, and the basis for their selective antifungal activity.      ","ACTIVITY":"R01","ADMINISTERING_IC":"AI","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"06/03/2014","BUDGET_START":"07/01/2014","BUDGET_END":"06/30/2015","CFDA_CODE":"855","CORE_PROJECT_NUM":"R01AI051629","ED_INST_TYPE":"SCHOOLS OF ARTS AND SCIENCES","FOA_NUMBER":"PA-10-067","FULL_PROJECT_NUM":"5R01AI051629-10","FUNDING_ICs":"NIAID:354288\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES","NIH_SPENDING_CATS":"","ORG_CITY":"PORTLAND","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"CHEMISTRY","ORG_DISTRICT":"03","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"PORTLAND STATE UNIVERSITY","ORG_STATE":"OR","ORG_ZIPCODE":"972070751","PHR":" Bacteria produce a small family of chemically related natural products such as fostriecin and phoslactomycin with established anticancer and antifungal activity. This project will combine modern techniques such as genetic engineering, organic and enzyme-catalyzed synthesis to 1) understand how these natural products are made, and 2) generate new structurally-related compounds for potential application in human-health issues.         ","PI_IDS":"1883144;","PI_NAMEs":"REYNOLDS, KEVIN A;","PROGRAM_OFFICER_NAME":"FRANCESCHI, FRANCOIS J","PROJECT_START":"03/01/2002","PROJECT_END":"06/30/2015","PROJECT_TERMS":"Affect;Anabolism;analog;Antifungal Agents;Aspergillosis;Aspergillus fumigatus;Bacteria;base;Biochemical;Biochemical Genetics;Biological;Biological Factors;Chemicals;cytotoxicity;Dehydration;DNA;DNA Sequence;Enzymes;Exhibits;Family;Fermentation;fostriecin;Gene Cluster;Generations;Genetic;Genetic Engineering;Glucans;Health;Human;Hybrids;hydroxyl group;inorganic phosphate;Kinetics;Knowledge;Lactones;leustroducsin B;Libraries;member;Modification;Molecular Target;mutant;Names;Nature;pathogen;Pathway interactions;pi bond;polyketide synthase;Process;Reaction;Role;Sequence Analysis;Series;Skeleton;small molecule libraries;Structure;System;Techniques;Testing;tool;uptake;Variant;Work","PROJECT_TITLE":"Phoslactomycins: Biosynthesis &Activity","SERIAL_NUMBER":"51629","STUDY_SECTION":"SBCB","STUDY_SECTION_NAME":"Synthetic and Biological Chemistry B Study Section","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"10","TOTAL_COST":"354288","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8889472","ABSTRACT_TEXT":"DESCRIPTION (provided by applicant):  The overall theme of the Berkeley Superfund Research Program (SRP) is using state-of-the-art technology, including 'omics'and nanotechnology, to (1) develop biological markers and apply them in human population studies, especially those involving susceptible populations such as children and pregnant women;(2) to improve chemical detection;and, (3) facilitate and lower the cost of waste site remediation. The proposed program builds on the strengths of UC Berkeley and Lawrence Berkeley National Laboratory in engineering, chemistry, and molecular epidemiology. The highly integrated program consists of six interrelated projects (three with a biomedical research focus and three with a non-biomedical research focus) and four cores. Our research team will focus on environmental exposures currently encountered at hazardous waste sites and several contaminants of emerging human health concern. All SRP mandates will be addressed. Projects 1, 2, 3 and 6 specifically aim to develop advanced techniques for the detection, assessment, and evaluation of the effect of hazardous substances on human health and improve methods to assess the risks to human health presented by benzene, arsenic, trichloroethylene and other hazardous substances. Project 5 will use nanotechnology to develop methods to detect hazardous substances in the environment in a simple, inexpensive fashion. Projects 4 and 6 will develop biological, chemical, and physical methods to remediate waste sites and reduce the amount and toxicity of hazardous substances. A Genomics and Analytical Chemistry core (C) and a Quantitative Biology core (D) will assist project researchers in meeting their goals. A Research Translation core (B) will facilitate intensive discussions between investigators and government audiences, and generate new initiatives to increase understanding of the significance and applicability of research to public health protection. The overall goal is to enhance understanding of the relationship between exposure and disease;provide usable tools to improve human health risk assessments;and, develop a range of prevention and remediation strategies to improve and protect public health and the environment. The program will be overseen and coordinated by an Administration core (A).","ACTIVITY":"P42","ADMINISTERING_IC":"ES","APPLICATION_TYPE":"3","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"07/28/2014","BUDGET_START":"04/01/2014","BUDGET_END":"03/31/2015","CFDA_CODE":"143","CORE_PROJECT_NUM":"P42ES004705","ED_INST_TYPE":"SCHOOLS OF PUBLIC HEALTH","FOA_NUMBER":"RFA-ES-09-012","FULL_PROJECT_NUM":"3P42ES004705-27S1","FUNDING_ICs":"NIEHS:49500\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES","NIH_SPENDING_CATS":"","ORG_CITY":"BERKELEY","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"PUBLIC HEALTH &PREV MEDICINE","ORG_DISTRICT":"13","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF CALIFORNIA BERKELEY","ORG_STATE":"CA","ORG_ZIPCODE":"947045940","PHR":"A highly integrated research and translation program is proposed with the goal of enhancing our  understanding ofthe relationship between environmental exposures and disease, providing usable tools to  improve human health risk assessments and developing prevention and remediation strategies to improve  and protect public health and the environment. State-of-the art technologies will be developed and applied to  meet these goals.","PI_IDS":"1883460;","PI_NAMEs":"SMITH, MARTYN T;","PROGRAM_OFFICER_NAME":"HEACOCK, MICHELLE ","PROJECT_START":"04/01/1997","PROJECT_END":"03/31/2016","PROJECT_TERMS":"Address;Analytical Chemistry;Arsenic;Basic Science;Benzene;Biological;Biological Markers;Biology;Biomedical Research;Bioremediations;Chemicals;Chemistry;Child;cost;Detection;Disease;Engineering;Environment;Environment and Public Health;Environmental Exposure;Evaluation;functional genomics;Genes;Genomics;Goals;Government;Hazardous Substances;Hazardous Waste Sites;Health;Health protection;Human;human population study;improved;interest;Intervention;Knowledge;Laboratories;Life;Measures;meetings;Mercury;Methods;Molecular Epidemiology;Nanotechnology;novel;oxidation;Poisons;Policies;Population;Predisposition;Pregnant Women;Prevention;programs;public health medicine (field);remediation;Research;Research Personnel;Risk;Risk Assessment;Scientist;Site;Superfund;superfund chemical;Techniques;Technology;Technology Transfer;tool;Toxic effect;Translating;Translational Research;Trichloroethylene;wasting","PROJECT_TITLE":"Toxic Substances in the Environment","SERIAL_NUMBER":"4705","STUDY_SECTION":"ZES1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"S1","SUPPORT_YEAR":"27","TOTAL_COST":"49500","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8634129","ABSTRACT_TEXT":"Project I - Zhang &Chen Program Director/Principal Investigator (Last, First, Middle): Lipton, Stuart A.  PROJECT SUMMARY (See instructions):  The N-methyl-D-aspartate subtype of gluatmate receptor (NMDAR) is essential for normal function of the central nervous system (CNS). However, excessive activation of NMDARs, particulariy of extrasynaptic as opposed to synaptic receptors, mediates, at least in part, neuronal or synaptic damage in many neurological disorders, such as hypoxic-ischemic brain injury and, as recently suggested, in Down syndrome. Blockade of excessive NMDAR activity must be achieved without interference with its normal brain function. We have taken two approaches for clinically-tolerated pharmacological and genetic intervention on NMDARs. One approach is to use Memantine but also NO species to further down regulate the NMDAR by S-nitrosylation.  The structural determinants on NMDARs for the action of Memantine and NO-like species will be characterized further under the auspices of this grant. Another approach is to utilize the inhibitory effect of a novel family of NMDAR subunits, composed of NRSA and NRSB, to downregulate NMDARs by affecting channel permeability, in a sense mimicking the effect of the NMDAR antagonist drugs that are also being developed here. We will study the role of the MS domain of NRS subunits that downregulate activity of NMDARs and also design NRS ligand-binding domain (LBD)-based screening assays to discover new compounds that modulate NRS-containing receptors. These agents will be useful for characterizing NRS-containing receptors, and possibly for neuroprotection.  Accordingly, the Specific Aims of this proposal are as follows: 1) To study the effect of S-nitrosylation/redox modulation of the loose linker region between the amino-terminal domain (ATD) and the LBD of NMDARs by electrophysiology;2) To develop LBD-derived screening assays to screen for ligands selective for the NRS subunit of the NMDAR. These ligands will be further characterized and refined by secondary assays, chemical modification, and co-crystallization;3) To study the inhibitory effect of peptides derived from the out vestibule (MS) region of NRS subunits on NMDAR permeability.","ACTIVITY":"P01","ADMINISTERING_IC":"HD","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"03/26/2014","BUDGET_START":"03/01/2014","BUDGET_END":"02/28/2015","CFDA_CODE":"","CORE_PROJECT_NUM":"P01HD029587","ED_INST_TYPE":"","FOA_NUMBER":"PAR-10-245","FULL_PROJECT_NUM":"5P01HD029587-19","FUNDING_ICs":"NICHD:371120\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT","NIH_SPENDING_CATS":"","ORG_CITY":"LA JOLLA","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"49","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"SANFORD-BURNHAM MEDICAL RESEARCH INSTIT","ORG_STATE":"CA","ORG_ZIPCODE":"920371005","PHR":"RELEVANCE (See instructions):  This grant aims to develop novel, clinically-tolerated NMDA receptor antagonists, called NitroMemantines, in addition to other novel molecules based on the structure of the NRS subunit, which this Team of Investigators discovered, in order to prevent cognitive deficits seen in Down syndrome. We take two approaches, pharmacological and genetic, for safe inhibition of NMDARs to treat pathological conditions without interference with normal function.","PI_IDS":"1861167;","PI_NAMEs":"LIPTON, STUART A;","PROGRAM_OFFICER_NAME":"","PROJECT_START":"","PROJECT_END":"","PROJECT_TERMS":"Abate;Active Sites;Affect;Affinity;Alzheimer's Disease;base;Binding (Molecular Function);Biological Assay;Brain;Brain Hypoxia-Ischemia;Brain Injuries;Calcium;Chemicals;Cognitive deficits;Crystallization;Cysteine;design;developmental disease/disorder;Down Syndrome;Electrophysiology (science);Etiology;Family;Functional disorder;gene therapy;Genetic;Glutamate Receptor;Grant;high throughput screening;Impaired cognition;improved;In Vitro;in vivo;Instruction;intellectual and developmental disability;Ion Channel;Ischemic-Hypoxic Encephalopathy;Knowledge;Ligand Binding Domain;Ligands;Magnesium;Mediating;Memantine;Modification;Molecular;Molecular Analysis;N-Methyl-D-Aspartate Receptors;N-Methylaspartate;National Research Service Awards;nervous system disorder;Neuraxis;Neurons;neuroprotection;Neuroprotective Agents;NMDA receptor antagonist;novel;NR1 gene;Oxidation-Reduction;Peptides;Perinatal Hypoxia;Permeability;Pharmaceutical Preparations;prevent;Principal Investigator;programs;Property;protein function;Reaction;receptor;Research Personnel;Role;screening;Single Nucleotide Polymorphism;Site;Site-Directed Mutagenesis;Structure;Sulfhydryl Compounds;Synapses;Synaptic Receptors;Testing;Therapeutic;Vertebral column;Vestibule","PROJECT_TITLE":"PROJECT 1 - MOLECULAR ANALYSIS OF NMDA RECEPTOR MODULATORY SITES","SERIAL_NUMBER":"29587","STUDY_SECTION":"ZHD1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"7044","SUFFIX":"","SUPPORT_YEAR":"19","TOTAL_COST":"","TOTAL_COST_SUB_PROJECT":"371120"}
{"APPLICATION_ID":"8927816","ABSTRACT_TEXT":"DESCRIPTION (provided by applicant): RNA functions as the central conduit for information transfer in biology - in simple replicating entities like RNA viruses and in complex multi-cellular organisms. RNA is uniquely able to play this role because it encodes information at two levels: in its linear primary sequence and in its ability to form functionally critical higher-order folds. Work to date, largely focused on intensive study of a few specific regulatory motifs, has revealed that RNA secondary and tertiary structures regulate splicing, translation and protein folding, binding by small ligands and drugs and proteins, and collapse into large-scale structural domains. There are only a small number of examples in which genome-scale RNA structures have been characterized. However, numerous new biological insights were uncovered in each case. RNA viruses are especially informative systems because their compact genomes feature a dense array of functionally important secondary and tertiary structure elements. Moreover, every identification of a new regulatory motif in a pathogenic virus presents a unique target for anti-virus therapeutic design. Guided by several years of preliminary and exploratory studies, we are poised to make very high- throughput and high-content RNA secondary and tertiary structure analysis straightforward. We will apply newly invented massively parallel secondary and tertiary structure constraint-generation technologies coupled with novel molecular dynamics-driven structural refinement to understand the biological roles of higher-order structure in the hepatitis C virus (HCV) RNA genome. Our Specific Aims are designed to reveal numerous new roles for RNA structure in the replication cycle of HCV, to do so in a way likely to inform many fields of biology, to make possible new therapeutic strategies for inhibiting viral replication, and to create tools that can be widely adopted by non-expert laboratories for analysis of complex, biologically authentic RNAs. Aim 1: Analyze the structure of three representative HCV RNA genomes using SHAPE, detected by massively parallel sequencing, to identify conserved base pairing and tertiary structure motifs. Aim 2: Create and validate an accurate and scalable approach for using experimental base pairing and through-space tertiary constraints to drive three-dimensional fold refinement for large RNAs. Aim 3: Integrate the technologies developed in this work to refine three-dimensional structure models and to discover new regulatory motifs for plus-sense HCV RNA genomes.","ACTIVITY":"R01","ADMINISTERING_IC":"GM","APPLICATION_TYPE":"3","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"09/23/2014","BUDGET_START":"04/01/2014","BUDGET_END":"03/31/2015","CFDA_CODE":"859","CORE_PROJECT_NUM":"R01GM064803","ED_INST_TYPE":"SCHOOLS OF ARTS AND SCIENCES","FOA_NUMBER":"PA-11-260","FULL_PROJECT_NUM":"3R01GM064803-10S1","FUNDING_ICs":"NIGMS:50000\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES","NIH_SPENDING_CATS":"","ORG_CITY":"CHAPEL HILL","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"CHEMISTRY","ORG_DISTRICT":"04","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIV OF NORTH CAROLINA CHAPEL HILL","ORG_STATE":"NC","ORG_ZIPCODE":"275990001","PHR":"PUBLIC HEALTH RELEVANCE: The hepatitis C virus (HCV) is a major worldwide health threat that causes fatal liver diseases and leads to two-thirds of all liver transplants and more than 50% of all liver cancers. This work will determine structures for complete HCV RNA genomes using innovative technologies created in the two collaborating project laboratories. This work is significant because it will create tools that can be widely adopted by non-expert laboratories for analysis of complex, biologically authentic RNAs;will reveal numerous new roles for RNA structure in HCV pathogenesis;and will identify novel frameworks for designing new antiviral therapeutics.","PI_IDS":"1860696;","PI_NAMEs":"WEEKS, KEVIN M;","PROGRAM_OFFICER_NAME":"SAKALIAN, MICHAEL ","PROJECT_START":"05/01/2002","PROJECT_END":"03/31/2017","PROJECT_TERMS":"Acylation;Adopted;Antiviral Agents;Base Pairing;Binding (Molecular Function);Biological;Biology;Communities;comparative;Complex;Coupled;Data;Data Set;design;Elements;Gene Expression Regulation;Generations;Genome;Health;Hepatitis C virus;Higher Order Chromatin Structure;Hydroxyl Radical;Individual;innovation;innovative technologies;insight;Laboratories;Lead;Ligands;Liver diseases;liver transplantation;Malignant neoplasm of liver;Massive Parallel Sequencing;Modeling;molecular dynamics;next generation;novel;novel strategies;novel therapeutics;Nucleotides;Organism;Pathway interactions;Pharmaceutical Preparations;Play;Primer Extension;protein folding;Proteins;reconstruction;Regulation;Research Personnel;research study;RNA;RNA Interference;RNA Splicing;RNA Viruses;Role;Science;structural biology;Structure;System;Technology;Therapeutic;three dimensional structure;tool;Translations;Viral;viral RNA;virology;Virus;Virus Diseases;virus pathogenesis;Work","PROJECT_TITLE":"Genome-Scale Analysis of RNA Virus Tertiary Structure","SERIAL_NUMBER":"64803","STUDY_SECTION":"MSFC","STUDY_SECTION_NAME":"Macromolecular Structure and Function C Study Section","SUBPROJECT_ID":"","SUFFIX":"S1","SUPPORT_YEAR":"10","TOTAL_COST":"50000","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8693935","ABSTRACT_TEXT":"The goal of the Cancer Disparities Program (CD) is to foster and sustain an integrated transdisciplinary environment for dedicated multi-level and multi-ethnic cancer disparities research that studies mechanisms and interventions from prevention through survivorship. The Program research emphasizes disparities affecting the region's largest ethnic populations, Latinos and Asians, engages intensively with the African American community, and includes other groups that are affected by disparities such as those who have limited English proficiency. Based on a shared understanding of the multi-level nature of these disparities and the interventions to reverse their course, the Program themes are: (A) Biologic determinants of cancer disparities;(B) Individual behavioral/psychological factors, emphasizing culture, language, and social context;and (C) healthcare and other systems factors, including interventions for systems change to reduce cancer disparities. CD is led by Dr. Rena Pasick, whose career has been dedicated to conducting social and behavioral research in cancer disparities among multi-ethnic populations, and to training a diverse cadre of cancer disparities population scientists;and Dr. Tung Nguyen, a clinician researcher with scientific expertise in Asian American cancer disparities and community-based participatory research. The Program has 24 members who have published 399 peer-reviewed papers in the past five years;15% were intra- and 16% were inter-programmatic publications. Annual extramural funding (total costs, 2010) is $10,476,370 in peer-reviewed support, nearly double the amount at the last review;total non-peer reviewed support is $1,631,255.    The Program also adds value to the Helen Diller Family Comprehensive Cancer Center (Center) by bringing expertise in diverse populations to clinical programs;by connecting community members and clinicians;by fostering the intra-programmatic and inter-programmatic collaborations that advance knowledge in cancer disparities;and by conducting significant and successful training programs to increase the number of researchers who are under-represented minorities. Future directions include expansion of the Program via new and continuing multi-component grants, addition of members through recruitment and advancement of junior faculty, increased collaboration with clinical programs, and development of a multi-cultural communication shared resource.","ACTIVITY":"P30","ADMINISTERING_IC":"CA","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"08/15/2014","BUDGET_START":"06/01/2014","BUDGET_END":"05/31/2015","CFDA_CODE":"","CORE_PROJECT_NUM":"P30CA082103","ED_INST_TYPE":"","FOA_NUMBER":"PAR-11-005","FULL_PROJECT_NUM":"5P30CA082103-16","FUNDING_ICs":"NCI:143\\","FUNDING_MECHANISM":"Research Centers","FY":"2014","IC_NAME":"NATIONAL CANCER INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"SAN FRANCISCO","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"12","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIVERSITY OF CALIFORNIA, SAN FRANCISCO","ORG_STATE":"CA","ORG_ZIPCODE":"941430962","PHR":"","PI_IDS":"2446782;","PI_NAMEs":"MCCORMICK, FRANK PATRICK;","PROGRAM_OFFICER_NAME":"","PROJECT_START":"","PROJECT_END":"","PROJECT_TERMS":"Address;Affect;African American;Aleurites;Area;Asian Americans;Asians;Awareness;base;Basic Science;Behavioral;Behavioral Research;Behavioral Sciences;Cancer Burden;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Control Research;cancer health disparity;cancer prevention;career;Catchment Area;Chinese People;Cities;Clinic;Clinical;Clinical Sciences;Collaborations;Communication;Communities;community based participatory research;Comprehensive Cancer Center;cost;County;demographics;Detection;Development;Discipline of Nursing;effective intervention;Environment;Ethnic group;Ethnicity aspects;experience;Extramural Activities;Faculty;Family;Filipino;Fostering;Funding;Future;Goals;Grant;Health;Healthcare;Hispanics;Immigrant;Incidence;Individual;International;Intervention;Knowledge;Laboratories;Language;Latino;Low income;Malignant Neoplasms;medical schools;member;Methods;Minority;Mortality Vital Statistics;Names;Nature;Paper;Patients;Peer Review;Pharmacy facility;Policies;Population;Population Group;Population Heterogeneity;Population Sciences;Positioning Attribute;Prevalence;Preventive Intervention;Process;Program Development;programs;Psychological Factors;Publications;Publishing;Race;Research;research and development;Research Personnel;research study;Research Training;Resource Sharing;safety net;San Francisco;Science;Scientist;social;Social Environment;Societies;socioeconomics;Students;survivorship;System;Training;Training Programs;Underrepresented Minority;Work","PROJECT_TITLE":"Cancer Disparities","SERIAL_NUMBER":"82103","STUDY_SECTION":"NCI","STUDY_SECTION_NAME":"Subcommittee B - Comprehensiveness","SUBPROJECT_ID":"6391","SUFFIX":"","SUPPORT_YEAR":"16","TOTAL_COST":"","TOTAL_COST_SUB_PROJECT":"143"}
{"APPLICATION_ID":"8681557","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): Stroke is the leading cause of adult disability in the U.S. and the third leading cause of mortality world-wide. The most common form, ischemic stoke, is caused by blood clots occluding arterial supply, resulting in permanent neurological damage or death. For a minority of patients, blood clots can be removed or lysed to prevent or limit stroke injury. However, neuroprotectants that improve survival and recovery are not available. Following arterial occlusion, neuronal death spreads outward from the initial infarct as neurons depolarize causing massive glutamate release and hyperactivation of NMDA receptors (NMDAR). As a result, excitotoxic Ca2+ flows into cells where it activates the protease calpain. This excitotoxic cascade is a major component of stroke pathophysiology. However, efforts to block the cascade with NMDAR antagonists have not proven effective in clinical trials due to unwanted effects. We discovered that the protein kinase Cdk5 physically links calpain to the NR2B subunit of NMDARs. Cdk5 is also bound to its activator p35. Through this NR2B-calpain- Cdk5/p35 signaling complex, excitotoxic activation of NMDARs causes calpain to convert p35 to p25. Cdk5 associated with p25 causes neuronal death and has been suggested to mediate to ischemic injury. However little is yet known of how Cdk5 or p35/p25 contributes to stroke pathophysiology or how it may be effectively targeted to improve outcome. Here we propose to characterize the dysregulation of Cdk5 following middle cerebral artery occlusion (MCAO) and determine the neuroprotective effects of loss of Cdk5 or p35 in mice. As a novel strategy to achieve neuroprotection we will target the NR2B-calpain-Cdk5/p35 cascade by identifying functional protein-protein interaction motifs and developing small interfering peptides (SIPs) that prevent calpain-Cdk5 and NR2B-Cdk5 interactions. These SIPs will be optimized as molecules that potently and specifically dissociate the NR2B-calpain-Cdk5/p35 and prevent Cdk5/p25 generation by NMDAR hyperactivation without otherwise affecting the functions of the receptors, calpain, or Cdk5. We will then assess their ability to neuroprotect and improve behavioral and histological outcome in mice subjected to MCAO. These translational studies will advance our knowledge of the mechanisms that mediate stroke injury and derive novel neuroprotectants that will potentially lead to the development of therapies that improving recovery and reduce stroke-related disability.        ","ACTIVITY":"R01","ADMINISTERING_IC":"NS","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"05/28/2014","BUDGET_START":"07/01/2014","BUDGET_END":"06/30/2015","CFDA_CODE":"853","CORE_PROJECT_NUM":"R01NS073855","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"PA-10-067","FULL_PROJECT_NUM":"5R01NS073855-03","FUNDING_ICs":"NINDS:344335\\","FUNDING_MECHANISM":"Research Projects","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE","NIH_SPENDING_CATS":"","ORG_CITY":"DALLAS","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"PSYCHIATRY","ORG_DISTRICT":"30","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UT SOUTHWESTERN MEDICAL CENTER","ORG_STATE":"TX","ORG_ZIPCODE":"753909105","PHR":" While stroke is a leading cause of morbidity and mortality, treatments that improve recovery are extremely limited. We will characterize the contribution of the protein kinase Cdk5 and its activating cofactor p35 to stroke injury and develop novel neuroprotectants that disrupt the excitotoxic cascade and prevent Cdk5 from contributing to neuronal death without adversely affecting essential NMDA receptor function. Thus we will provide mechanistic insight to a critical component of stroke injury and derive novel neuroprotectants that may be translated into therapies that limit stroke injury and facilitate recovery.            ","PI_IDS":"1870467;","PI_NAMEs":"BIBB, JAMES A;","PROGRAM_OFFICER_NAME":"BOSETTI, FRANCESCA ","PROJECT_START":"07/01/2012","PROJECT_END":"06/30/2017","PROJECT_TERMS":"Ablation;Adult;Affect;alternative treatment;artery occlusion;Behavioral;Binding (Molecular Function);Biochemical;Blood coagulation;brain tissue;Calpain;Cause of Death;CDK5 gene;Cells;Cessation of life;Clinical;Clinical Trials;cofactor;Complex;Coupled;Cytolysis;Data;defined contribution;disability;excitotoxicity;functional disability;Functional disorder;Generations;Genetic;Glutamates;Histopathology;Holoenzymes;improved;In Vitro;Infarction;Injury;insight;Ischemic Penumbra;Ischemic Stroke;Knowledge;Lead;Link;Mediating;Membrane;Middle Cerebral Artery Occlusion;Minority;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Mus;N-Methyl-D-Aspartate Receptors;Nervous System Physiology;Nervous System Trauma;Neurons;neuroprotection;Neuroprotective Agents;neurotoxicity;NMDA receptor antagonist;novel;novel strategies;Outcome;Patients;Pattern;Peptide Hydrolases;Peptides;Phosphotransferases;Physiological;prevent;Protein Kinase;protein protein interaction;receptor function;Recovery;response;Role;Severities;Signal Transduction;Specificity;stroke;Substrate Specificity;Testing;therapy development;Time;Translating;translational study;Viral","PROJECT_TITLE":"The Role of Cdk5 in Stroke","SERIAL_NUMBER":"73855","STUDY_SECTION":"NOMD","STUDY_SECTION_NAME":"Neural Oxidative Metabolism and Death Study Section","SUBPROJECT_ID":"","SUFFIX":"","SUPPORT_YEAR":"3","TOTAL_COST":"344335","TOTAL_COST_SUB_PROJECT":""}
{"APPLICATION_ID":"8651477","ABSTRACT_TEXT":"6.2 General Description  The Center for Environmental Health and Susceptibility is housed in the Gillings School of Global Public Health of UNC-CH, which occupies three adjacent, connected buildings: Rosenau Hall, McGavran-Greenberg Hall, and the Michael Hooker Research Center. The CEHS's administrative offices occupy a suite of offices and a conference room encompassing 1000 square feet in Rosenau Hall. Facilities available to the Center include several laboratories ranging from ~800-4000 sq. ft. in size, located in several buildings of the Schools of Medicine and Public Health, and in the Lineberger Comprehensive Cancer Center. Detailed information about specific resources and capabilities corresponding to each Facility Core are described in the respective documents in this application. In addition to its own Facility Cores, the CEHS will continue utilizing existing core facilities from diverse UNC-CH's Schools, Centers and Institutes. The fact that all the biomedical Schools, Centers and Institutes are located very close to each other on the campus, facilitates the atmosphere of mutual support and collaboration.    6.2.1 Organizational Changes  The Administrative Core is responsible for providing leadership to the Center to ensure optimal performance and efficient coordination and integration of all its components and activities. After eight years of successful research-proofing activities, the Center is making three important organizational changes in order to advance to a higher level of accomplishment of its mission: (a) Transition from Research Cores to Flexible Interdisciplinary Research Groups;(b) Reorganization and Enhancement of the Facility Cores;and (c) creation of a Research Navigator position.    These changes, depicted here and described in detail in other sections of the Application, were implemented in the last year of the current funding cycle, expecting to have the new structure and function in full operation by the beginning of the new funding cycle. This approach is meant to provide first hand experience with the proposed enhanced Center, allowing an assessment of the new model to make adjustments by the start of the renewal grant.","ACTIVITY":"P30","ADMINISTERING_IC":"ES","APPLICATION_TYPE":"5","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"04/05/2014","BUDGET_START":"04/01/2014","BUDGET_END":"03/31/2015","CFDA_CODE":"","CORE_PROJECT_NUM":"P30ES010126","ED_INST_TYPE":"","FOA_NUMBER":"RFA-ES-09-002","FULL_PROJECT_NUM":"5P30ES010126-14","FUNDING_ICs":"NIEHS:287373\\","FUNDING_MECHANISM":"Research Centers","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES","NIH_SPENDING_CATS":"","ORG_CITY":"CHAPEL HILL","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"04","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"UNIV OF NORTH CAROLINA CHAPEL HILL","ORG_STATE":"NC","ORG_ZIPCODE":"275990001","PHR":"","PI_IDS":"1898586;","PI_NAMEs":"SWENBERG, JAMES A;","PROGRAM_OFFICER_NAME":"","PROJECT_START":"","PROJECT_END":"","PROJECT_TERMS":"Advisory Committees;Collaborations;Communities;Comprehensive Cancer Center;Core Facility;Decision Making;Effectiveness;Ensure;Environmental Health;experience;flexibility;Funding;Goals;Grant;Housing;Institutes;Interdisciplinary Study;Laboratories;Leadership;medical schools;meetings;member;Mission;Modeling;National Institute of Environmental Health Sciences;North Carolina;operation;Organizational Change;Performance;Pilot Projects;planetary Atmosphere;Positioning Attribute;Predisposition;Productivity;programs;public health medicine (field);Research;Research Personnel;Resources;Schools;square foot;Structure;symposium;Universities","PROJECT_TITLE":"Core A: Administrative Core","SERIAL_NUMBER":"10126","STUDY_SECTION":"EHS","STUDY_SECTION_NAME":"Environmental Health Sciences Review Committee","SUBPROJECT_ID":"7109","SUFFIX":"","SUPPORT_YEAR":"14","TOTAL_COST":"","TOTAL_COST_SUB_PROJECT":"287373"}
{"APPLICATION_ID":"8715999","ABSTRACT_TEXT":"3.1. Qualifications &Roles of the PO and PC. This Core will be led by Dr. Shaikh who is the Principal Investigator (PI) of the grant and will serve as the PO of the RI-INBRE program. As PO, he will foster the recruitment and research career development of junior faculty and promote collaborative biomedical research among the junior and senior faculty from the network institutions. He is a member of the Executive Committee of the NECC which coordinates the ongoing 5-state INBRE collaboration for providing high-speed fiber optic connectivity between various academic institutions and health centers within each state and in the northeastern region. His administrative experience consists of continuously serving as the Chair of the Department of Pharmacology and Toxicology, and later the Department of Biomedical Sciences, at URI's College of Pharmacy for 18 years. Currently, he is the Director of the Center for Molecular Toxicology and the statewide, multi-institutional RI-INBRE Program, which he has directed since its inception in 2001. He was formerly a member of NIH's Toxicology Study Section and has remained active as an ad hoc reviewer for NIH grant review panels. He has been an NIH grantee since 1975 and has a long-term research interest in metal toxicology. More recently, he has been interested in elucidating the molecular mechanisms of the xenoestrogenic effects of cadmium in breast cancer progression. Dr. Shaikh's research expertise is pertinent to the scientific themes of the proposal and he possesses the administrative skills necessary to lead the Rl- INBRE progra0 for the next 5 years. With the assistance of the PC and the advisory committees (EAC, SC, and SEC), he will ensure that the network prospers and progress is made in all Specific Aims proposed in this proposal.    The PC, Dr. Parang, is an alumnus of the RI-INBRE program. He assumed the PC responsibilities in June 2012 and has been intimately involved in developing the present proposal with the PD. After graduation from the RI-INBRE program in 2004, he remained engaged with the program by organizing a seminar series and as a mentor in the SURF program. He has been deeply involved in RI-INBRE administrative activities, such as organizing Mentoring Committee meetings and a grant workshop, reviewing research proposals for potential inclusion in the program, participating in meetings with the URI administrators, EAC, SC regarding RI-INBRE matters, and planning the thematic focus areas based on research strengths among the network faculty. His scientific interests are in drug discovery and development for cancer and neurological diseases, expertise that is highly pertinent to the proposed scientific themes of this grant application, and also compliment the PO's expertise in Molecular Toxicology. Dr. Parang has research collaborations at URI, Brown, nationally, and internationally. His research can be appropriately described as the application of synthetic organic chemistry to problems in biology. Specific areas currently under investigation include: 1) using peptides as cell-penetrating molecular transporters in anticancer drug delivery;2) designing protein kinase inhibitors as anticancer agents;and 3) developing neuroprotective agents for neurodegenerative diseases. Dr. Parang will assist Dr. Shaikh in overseeing various aspects of the network, particularly its research and faculty mentoring programs. He will also spearhead the research activities in the thematic areas through improving collaboration between network institutions and organizing the seminar series and symposia.","ACTIVITY":"P20","ADMINISTERING_IC":"GM","APPLICATION_TYPE":"2","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"05/21/2014","BUDGET_START":"06/01/2014","BUDGET_END":"04/30/2015","CFDA_CODE":"","CORE_PROJECT_NUM":"P20GM103430","ED_INST_TYPE":"","FOA_NUMBER":"PAR-12-205","FULL_PROJECT_NUM":"2P20GM103430-14","FUNDING_ICs":"NIGMS:442178\\","FUNDING_MECHANISM":"Research Centers","FY":"2014","IC_NAME":"NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES","NIH_SPENDING_CATS":"","ORG_CITY":"KINGSTON","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"","ORG_DISTRICT":"02","ORG_DUNS":"","ORG_FIPS":"","ORG_NAME":"UNIVERSITY OF RHODE ISLAND","ORG_STATE":"RI","ORG_ZIPCODE":"","PHR":"","PI_IDS":"1955260;","PI_NAMEs":"SHAIKH, ZAHIR A;","PROGRAM_OFFICER_NAME":"","PROJECT_START":"","PROJECT_END":"","PROJECT_TERMS":"Administrator;Advisory Committees;American Association for the Advancement of Science;Antibodies;Antineoplastic Agents;Applications Grants;Area;base;Biology;Biomedical Research;Cadmium;career;career development;Cells;Collaborations;college;design;Development;Drug Delivery Systems;drug development;drug discovery;Educational workshop;Ensure;Ethics;Evaluation;experience;Faculty;Fiber Optics;Fostering;Funding;Goals;Grant;Grant Review;Health;improved;Individual;Institution;instrumentation;interest;Investigation;Laboratories;Lead;Leadership;malignant breast neoplasm;Malignant Neoplasms;meetings;member;Mentors;Metals;Molecular;Molecular Toxicology;Monitor;nervous system disorder;Neurodegenerative Disorders;Neuroprotective Agents;Organic Chemistry;Outcome Assessment (Health Care);Peptides;Pharmacology and Toxicology;Pharmacy facility;Phase;Plasmids;Postdoctoral Fellow;Principal Investigator;Program Reviews;programs;protein kinase inhibitor;Protein Kinase Inhibitors;Reagent;Research;Research Activity;Research Infrastructure;Research Personnel;Research Project Grants;Research Proposals;Rhode Island;Role;Science;Series;skills;Speed (motion);Students;Study Section;symposium;Toxicology;Training;transporter (molecular);tumor progression;United States National Institutes of Health;Writing","PROJECT_TITLE":"Administration Core","SERIAL_NUMBER":"103430","STUDY_SECTION":"ZGM1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"7034","SUFFIX":"","SUPPORT_YEAR":"14","TOTAL_COST":"","TOTAL_COST_SUB_PROJECT":"442178"}
{"APPLICATION_ID":"8762880","ABSTRACT_TEXT":"    DESCRIPTION (provided by applicant): This application is for Dr. Sanjay Basu, a physician-epidemiologist establishing himself in the field of statistical and modeling research on cardiovascular disease disparities. This award will allow Dr. Basu to: (1) develop a career focus in nutritional epidemiology and cardiovascular disease disparities;(2) learn how to implement \"systems science\" mathematical modeling methods that simulate the impact of cardiovascular disease interventions;and (3) gain the necessary content expertise to address major unanswered questions in the epidemiology of cardiovascular disease disparities. To achieve these goals, Dr. Basu has assembled a mentoring team with expertise on nutrition and its relationship to cardiovascular disease risk;the epidemiology of cardiovascular disease disparities;and mathematical modeling. Dr. Basu's research proposal addresses disparities in the prevalence of hypertension between groups of different socioeconomic status (SES). The Institute of Medicine (IOM) has declared lower sodium consumption to be a national goal to reduce hypertension-related cardiovascular disease.2 Dr. Basu's research will test hypotheses about the relationship between social factors and sodium consumption among low-SES populations experiencing the highest prevalence of uncontrolled hypertension.3 In Aim 1, a regression tree analysis4 applied to the National Health and Nutrition Examination Survey will test the hypothesis that variations in sodium consumption within the population can be predicted using a few key sociodemographic variables.5 The analysis will identify what social factors can best explain heterogeneities in sodium intake within the US population. In Aim 2, we will then test the hypothesis that an economic program incentivizing low-SES populations to increase the number of times per month they go grocery shopping can lead high-sodium consumers to substitute packaged products with fresh produce, thereby lowering their sodium consumption.6-8 To better assess causality, we will analyze a unique \"quasi-natural experiment\" in Delaware, New Jersey and Pennsylvania in which a subset of households on food stamps were randomly allocated to receive benefits twice monthly instead of once monthly, which induced more frequent grocery shopping despite having the same overall monthly grocery budget as matched controls. The results of Aims 1 and 2 will be incorporated into a simulation model of hypertension in Aim 3. An agent-based model will be constructed to compare the impact of the program in Aim 2 to two other programs- front-of-package nutrition labeling9 and a vegetable voucher plan10-that attempt to influence consumers to reduce sodium consumption. The model will estimate the impact and cost-effectiveness of the interventions for reducing national hypertension disparities. This will form the basis of an R01 application to study novel sodium reduction strategies that target consumer food choice behaviors. This proposal addresses NHLBI strategic plan challenge 3.1, which encourages social science research incorporating \"systems science\" modeling methods to investigate social factors and policy interventions to reduce health disparities.11        ","ACTIVITY":"K08","ADMINISTERING_IC":"HL","APPLICATION_TYPE":"1","ARRA_FUNDED":"N","AWARD_NOTICE_DATE":"07/11/2014","BUDGET_START":"09/01/2014","BUDGET_END":"08/31/2015","CFDA_CODE":"837","CORE_PROJECT_NUM":"K08HL121056","ED_INST_TYPE":"SCHOOLS OF MEDICINE","FOA_NUMBER":"PA-11-193","FULL_PROJECT_NUM":"1K08HL121056-01A1","FUNDING_ICs":"NHLBI:131652\\","FUNDING_MECHANISM":"Other Research Related","FY":"2014","IC_NAME":"NATIONAL HEART, LUNG, AND BLOOD INSTITUTE","NIH_SPENDING_CATS":"","ORG_CITY":"STANFORD","ORG_COUNTRY":"UNITED STATES","ORG_DEPT":"INTERNAL MEDICINE/MEDICINE","ORG_DISTRICT":"18","ORG_DUNS":"","ORG_FIPS":"US","ORG_NAME":"STANFORD UNIVERSITY","ORG_STATE":"CA","ORG_ZIPCODE":"943041222","PHR":"PUBLIC HEALTH RELEVANCE: Improving our understanding of the social factors and interventions that affect nutrition among low-SES populations is critical to effectively reducing disparities in cardiovascular disease. This study will specifically investigate what modifiable social factors and economic incentives may affect nutritional choice behaviors that influence sodium consumption. The research may help identify strategies to lower sodium intake among low- SES populations and reduce disparities in the prevalence of hypertension.            ","PI_IDS":"8190474;","PI_NAMEs":"BASU, SANJAY;","PROGRAM_OFFICER_NAME":"WRIGHT, JACQUELINE ","PROJECT_START":"09/01/2014","PROJECT_END":"08/31/2018","PROJECT_TERMS":"Address;Adult;Affect;Age;American;Area;Award;base;behavior influence;Behavioral;Blood Pressure;Budgets;Cardiovascular Diseases;cardiovascular disorder risk;cardiovascular risk factor;Cardiovascular system;career;Cessation of life;Choice Behavior;Consumption;cost effective;cost effectiveness;County;Data;Delaware;Diagnosis;Diet;Dietary intake;Dietary Intervention;Economic Factors;Economics;Educational aspects;Effectiveness of Interventions;Epidemiologist;Epidemiology;Ethnicity aspects;Etiology;experience;Food;Food Processing;Frequencies (time pattern);fruits and vegetables;Gender;Goals;Health;Health Care Costs;health disparity;Heterogeneity;High Prevalence;Household;Hypertension;Hypotension;improved;Incentives;Income;Individual;Institute of Medicine (U.S.);Intake;Interdisciplinary Study;Intervention;Intervention Studies;Knowledge;Label;Lead;Learning;Literature;Low income;low socioeconomic status;mathematical model;Mentors;Mentorship;Methods;Modeling;models and simulation;National Heart, Lung, and Blood Institute;Natural experiment;New Jersey;NHANES;novel;novel strategies;nutrition;Nutritional;nutritional epidemiology;Parents;Pennsylvania;Physicians;Policies;Population;Prevalence;Price;Product Packaging;programs;Race;randomized trial;Research;Research Proposals;Research Training;response;Science;Simulate;skills;social;social science research;Socioeconomic Status;Sodium;Sodium Chloride;Statistical Models;Strategic Planning;Subgroup;System;Techniques;Testing;Time;Training;Training Programs;Trees;Variant;Vegetables;voucher;Work","PROJECT_TITLE":"Studying social factors in sodium consumption to reduce hypertension disparities","SERIAL_NUMBER":"121056","STUDY_SECTION":"ZHL1","STUDY_SECTION_NAME":"Special Emphasis Panel","SUBPROJECT_ID":"","SUFFIX":"A1","SUPPORT_YEAR":"1","TOTAL_COST":"131652","TOTAL_COST_SUB_PROJECT":""}