ORG_CITY: BALTIMORE

ORG_NAME: BALTIMORE VA MEDICAL CENTER

ORG_STATE: MD

PHR: The long-term goal of my research is to understand the cellular and molecular mechanisms governing skeletal development, homeostasis and repair. One project examines fuel consumption by osteoblasts and osteocytes under normal conditions and in response to well-defined stimuli, which increase bone cell energy demands. Such information will help clarify how and why bone communicates with other energy consuming tissues, and may explain the close association between the existence of bone disease and diabetes in humans; which should have an immediate impact on the management, treatment and prevention of these related metabolic disturbances. In a second project, we are using novel approaches to characterize the timing of innervation, and the consequence of blocking nerve action on bone development and repair. These studies represent the first comprehensive approach to investigating the function of sensory nerves in bone.

PI_NAMEs: CLEMENS, THOMAS L (contact)

PROJECT_TERMS: Affect;afferent nerve;Alleles;Attenuated;Award;Axon;Biological Availability;Blood Vessels;bone;Bone callus;bone cell;Bone Development;Bone Diseases;bone fracture repair;bone repair;Bone structure;Bone Surface;career;Cells;Cisplatin;Communication;Consumption;Coupling;Diabetes Mellitus;Embryonic Development;Endocrine;Energy consumption;Energy Metabolism;Engineering;fatty acid metabolism;Femur;Fiber;Fracture;Genetic;global health;Glucose;Goals;Grant;Homeostasis;Human;Impairment;Insulin;Insulin Receptor;insulin secretion;Invaded;Length;Link;long bone;Macrophage;Metabolic;Metabolic Diseases;Metabolic Pathway;Metabolism;mineralization;Modeling;Molecular;mouse model;Mus;Mutation;Nerve Block;Nerve Fibers;Nerve Growth Factors;nerve supply;neuronal survival;Neuropathy;neurotrophic factor;Neurotrophic Tyrosine Kinase Receptor Type 1;novel;novel strategies;Organ;Osteoblasts;Osteocalcin;osteochondral tissue;Osteocytes;Osteoporosis;osteoprogenitor cell;oxidation;panacea;Pancreas;Pathway interactions;Penetration;Periosteum;Peripheral;Phenotype;Physiologic Ossification;Play;Population;postnatal;Prevention;Process;Production;progenitor;Receptor Protein-Tyrosine Kinases;Receptor Signaling;repaired;Research;response;revascularization;Role;Scientist;Sensory;Signal Transduction;skeletal;Skeletal Development;Skeleton;Stimulus;stromal progenitor;Structure;Tamoxifen;Time;Tissues;Tyrosine Kinase Receptor Inhibition;Ulna Fractures;United States National Institutes of Health;Vascularization;Walking

PROJECT_TITLE: BLR&D Research Career Scientist Award Application


ADMINISTERING_IC: VA

ARRA_FUNDED: N

FUNDING_MECHANISM: NON-SBIR/STTR RPGS

IC_NAME: Veterans Affairs

ORG_CITY: PORTLAND

ORG_COUNTRY: UNITED STATES

ORG_FIPS: US

ORG_NAME: PORTLAND VA MEDICAL CENTER

ORG_STATE: OR

PHR: Implementation of effective care coordination practices are a high priority for the VA and is the focus of two major national initiatives to address MISSION Act access to care goals. Prior research suggests enhancement of care coordination can improve appropriate access and outcomes, especially for complex, chronic care patients. In the VA, care coordination assessment and services vary across sites and evidence is lacking on whether Veterans who need the services receive them, and the extent to which they benefit when received. We will be guided by organizational theory and apply multiple methods in an observational study with a comparison group. Using routinely collected care coordination needs assessment data, supplemented with Veteran health care use data, and Veteran and provider perspectives, we will evaluate care coordination needs assessment tools and practices and their impacts on Veteran health care use, outcomes and costs.

PI_NAMEs: HYNES, DENISE M. (contact)

PROJECT_TERMS: Address;Adoption;Assessment tool;care coordination;care outcomes;care systems;Caring;Case Management;Categories;Chronic Care;Clinical;Communities;Community Healthcare;comparison group;Complex;Consult;cost;COVID-19 pandemic;Data;Data Sources;data warehouse;design;Development;Diffusion of Innovation;Electronic Health Record;Electronics;Elements;Emergency medical service;Ensure;Evaluation;evidence base;Evidence based practice;experience;Exposure to;formative assessment;Future;Goals;Group Interviews;Health;health assessment;health care availability;health care service;health service use;Health Services Accessibility;Health system;Healthcare;high risk;Hybrids;implementation facilitation;implementation strategy;improved;innovation;insight;integrated care;Interview;Life;Medicare;Methodology;Methods;migration;Modeling;mortality;multiple data sources;Needs Assessment;Nursing Care Management;Nursing Services;Observational Study;Office Nursing;Outcome;Outcome and Process Assessment;patient oriented;Patients;Perception;Primary Care;Process;Process Assessment;programs;Provider;psychosocial;Qualitative Methods;Reporting;Research;Research Design;Role;satisfaction;service coordination;Services;Site;Social Work;Surveys;System;telehealth;theories;tool;Trust;uptake;Veterans;Vital Status

PROJECT_TITLE: Care Coordination and Outcomes for High Risk Patients:  Building the Evidence for Implementation

STUDY_SECTION_NAME: HSR-5 Health Care System Organization and Delivery and Women's Health[HSR5]


FUNDING_MECHANISM: OTHERS

ORG_CITY: SAN FRANCISCO

ORG_NAME: VETERANS AFFAIRS MED CTR SAN FRANCISCO

ORG_STATE: CA

PHR: Our on-going research employs state-of-the-art technologies along with novel preclinical animal models to explore molecular and cellular mechanisms underlying the pathogeneses of several devastating diseases that afflict large populations of our VA patients, including osteoporosis, bone fracture, mineral imbalance, traumatic and ischemic brain injuries, and Alzheimer's Diseases. All of those diseases greatly impact on the quality of life of our veterans and impose substantial social and financial burden on the VA healthcare system and the entire VA community as a whole. Successful completion of our highly translational research projects will not only advance our understanding of how those diseases develop, but also lead to timely therapies to prevent and/or treat the diseases. Indeed, one of the concepts that we developed to repurpose 2 FDA-approved drugs for a new combined therapy for osteoporosis will soon be tested clinically by our VA colleague to treat VA patients afflicted with osteoporosis. If validated, this new therapy could be soon available clinically.

PI_NAMEs: CHANG, WENHAN  (contact)

PROJECT_TERMS: Ablation;Acute;Adult;Aging;Agonist;Alzheimer's Disease;Alzheimer's disease model;Animal Model;Animals;antagonist;anti-cancer research;Apoptosis;Apoptotic;Applications Grants;Automobile Driving;Award;base;Biochemical;Biology;Biomechanics;bone;Bone Diseases;bone fracture repair;Brain;Brain Diseases;brain research;Butyric Acids;Calcium-Sensing Receptors;Cardiovascular system;career;CCL4 gene;Cell Death;Cell Physiology;Cells;cellular imaging;Chondrocytes;Chronic;Clinical;Clinical Trials;Code;Combined Modality Therapy;Communities;Consultations;Coupled;CXCL11 gene;CYP27B1 gene;Data;Development;Disease;Disease of parathyroid glands;Early Onset Familial Alzheimer's Disease;Equilibrium;Excision;experimental study;extracellular;FDA approved;Financial Hardship;Fracture;Funding;Future;gamma-Aminobutyric Acid;gastrointestinal;Genes;genetic approach;genetic manipulation;healing;Healthcare Systems;Heterodimerization;Heterozygote;Homeostasis;Hormonal;Hormone secretion;hormone therapy;Hypercalcemia;Hyperparathyroidism;IGF1 gene;IGF1R gene;In Vitro;in vivo;Injections;International;Ischemia;Ischemic Brain Injury;Kidney Failure;Knockout Mice;Laboratories;LoxP-flanked allele;Lung;Malignant Neoplasms;Mammary gland;Manuscripts;Mediating;Mediator;Metabolic Diseases;Metabolism;Minerals;Modeling;Molecular;Molecular Structure;mouse model;Mus;Nature;Nerve Degeneration;neuron loss;Neurons;neuroprotection;neurotransmission;new combination therapies;novel;novel therapeutics;nutrient deprivation;Oklahoma;Organ;Osteoblasts;Osteoporosis;overexpression;Oxygen;Parathyroid gland;Pathogenesis;Pathologic;Patients;Pharmaceutical Preparations;pharmacologic;Pharmacologic Substance;Phenotype;Physiological;Play;Population;postnatal;pre-clinical;prenatal;Preparation;prevent;Production;Property;PTH gene;Publications;Quality of life;receptor;receptor-mediated signaling;Regimen;Research;Research Project Grants;Role;Scientist;Services;side effect;Signal Transduction;Signaling Molecule;skeletal;Skeletal Development;skeletal disorder;Skin;Small Inducible Cytokine B11;social;System;targeted treatment;Technology;Testing;Therapeutic;Time;Tissues;Translational Research;Traumatic Brain Injury;United States National Institutes of Health;Universities;Veterans;Vitamin D Deficiency

PROJECT_TITLE: BLR&D Research Career Scientist Award


PHR: U.S.  servicemen  and  women  encountered  malaria  during  the  Revolutionary  War  and  every  US  war since that time. Malaria and antimalarials are two of the most common biological and chemical  exposures  of  US  veterans.  Multidrug  resistant  parasites  have  spread  to  virtually  all  malarious  regions  of  the  world.  New  drug  strategies  for  prevention  and  treatment  of  malaria  are  urgently  needed. My lab is committed to the development of safe and effective drugs that can be used in  all  individuals,  regardless  of  their  station:  children,  adults,  men,  women,  pregnant,  unborn,  or  genetically deficient in the enzyme glucose 6- phosphate dehydrogenase (G6PD). The resultant  advantages  of  avoiding  drug  toxicity,  febrile  illness  and  complex  medical  management  during  deployment are self- evident, as are the benefits to both short and long- term health of the soldier.

PI_NAMEs: RISCOE, MICHAEL KEVIN (contact)

PROJECT_TERMS: 4-aminoquinoline;Adult;Anti-malarials;Antiparasitic Agents;atovaquone;Award;Babesia microti;Babesiosis;Biguanides;Biochemistry;Biological;Biological Availability;Biology;Blindness;Blood;Borrelia microti;career;Categories;Chemical Exposure;chemical synthesis;Chemicals;chemotherapy;Chemotherapy-Oncologic Procedure;Child;Chloroquine;co-infection;Collaborations;Complex;design;Development;Disease;Drug Design;drug mechanism;Drug toxicity;Enzymes;Eye diseases;Fetus;Fever;Glucosephosphate Dehydrogenase;Health;HIV;Immune;immunodeficiency;improved;In Vitro;in vivo;Individual;Infection;Injectable;Investigational Therapies;Laboratories;Lead;Legal patent;Liver;Lyme Disease;Malaria;Malaria prevention;Medical;Medical Research;Medicine;member;men;Methods;Mitochondria;Modernization;Molecular;mouse model;Multi-Drug Resistance;Neurological disability;New England;novel;novel therapeutics;Oral;Parasite resistance;Parasites;Parasitology;Patients;Peer Review;Persons;Pharmaceutical Preparations;Pharmacotherapy;Plasmodium falciparum;Predisposition;pregnant;Pregnant Women;prenatal;Prevention;Prevention strategy;Prodrugs;programs;Quinolones;Research;Research Institute;resistant strain;Respiration;respiratory;Risk;Scientist;Soldier;synergism;tick transmission;Time;Toxoplasma gondii;Toxoplasmosis;Transplant Recipients;Tropical Disease;United States;United States Department of Veterans Affairs;United States National Institutes of Health;Vascular blood supply;vector;Veterans;virtual;Vulnerable Populations;War;Woman

PROJECT_TITLE: BLR&D Research Career Scientist Renewal Award Application


ORG_CITY: SEATTLE

ORG_NAME: VA PUGET SOUND HEALTHCARE SYSTEM

ORG_STATE: WA

PHR: Heart failure causes significant morbidity and mortality. It is the most common discharge diagnosis for Veterans hospitalized in a VA healthcare system, and the annual mortality of Veterans with heart failure is 15%. Mutations in myosin heavy chain 7 (MYH7) are common causes of genetic cardiomyopathies that lead to heart failure. As genetic testing is increasingly performed, new MYH7 variants are continuously discovered; however, this is complicated by findings of variants of unknown significance and by lack of disease-modifying treatments. This proposal seeks to identify MYH7 variants that induce heart failure and then better understand the disease process in human heart cells. This precision medicine approach, in turn, may potentially lead to novel disease-modifying therapies for patients with heart failure due to MYH7 mutations.

PI_NAMEs: YANG, KAI-CHUN DANIEL (contact)

PROJECT_TERMS: Accounting;Address;Affect;American;Award;Biological Assay;Cardiac Myosins;cardiac tissue engineering;Cardiomyopathies;Caring;Cells;Clinical;clinically relevant;Co-Immunoprecipitations;Data;Development;Diagnosis;Dilated Cardiomyopathy;Disease;disease model;Dominant-Negative Mutation;EFRAC;Emotional;experimental study;familial dilated cardiomyopathy;Functional disorder;Future;gain of function;General Population;Genetic;Genetic Databases;genetic testing;Genomics;Goals;Guidelines;Healthcare Systems;heart cell;Heart failure;heart failure with reduced ejection fraction;high throughput screening;Hospitalization;Human;human disease;human induced pluripotent stem cells;Hypertrophic Cardiomyopathy;Impairment;improved;Induced Mutation;induced pluripotent stem cell;induced pluripotent stem cell derived cardiomyocytes;inherited cardiomyopathy;innovation;Intervention;Knock-out;Lead;loss of function;Mammalian Cell;Medical;Methods;Modeling;Morbidity - disease rate;mortality;Muscle;Mutagenesis;mutant;Mutation;Myosin ATPase;Myosin Heavy Chains;myosin-binding protein C;new therapeutic target;novel;overexpression;Pathogenesis;Pathogenicity;Patients;precision medicine;preservation;Process;protein degradation;Protein Isoforms;protein protein interaction;Proteins;Research;Ring Finger Domain;Risk;Rodent;Role;Susceptibility Gene;Techniques;Testing;Therapeutic Intervention;Thick Filament;Training;Two-Hybrid System Techniques;ubiquitin-protein ligase;Up-Regulation;Variant;variant of unknown significance;Veterans;Work;yeast two hybrid system;Yeasts

PROJECT_TITLE: Dissecting the mechanism of how dominant negative MYH7 mutations lead to genetic cardiomyopathies


ORG_CITY: CHICAGO

ORG_NAME: JESSE BROWN VA MEDICAL CENTER

ORG_STATE: IL

PHR: Multiple sclerosis (MS) is an autoimmune, inflammatory disease that is a common cause of disability in young adults. The VA provides care for approximately 16,000 MS patients a year, and 6,000 are service connected for this condition. The cost of caring for Veterans with MS is very high. Medications used to treat MS are only partially effective and very costly. The goals of our research are to identify ways to prevent tissue injury and enhance recovery in patients with MS and other inflammatory diseases. Using human immune cells and a mouse model of MS, we have identified novel signaling pathways that maintain cell survival during injury, decrease inflammation, and promote clinical recovery. The goals of this proposal are to examine how these signaling pathways work in human immune cells and how they prevent injury to neurons in the brain and spinal cord. These studies are also relevant to other types of brain diseases that are associated with inflammation such as traumatic brain injury, stroke, and Alzheimer's disease.

PI_NAMEs: CARRITHERS, MICHAEL D (contact)

PROJECT_TERMS: Alzheimer's Disease;Animal Model;Autoimmune;Bioenergetics;Biological Markers;Brain;Brain Diseases;Brain Injuries;Calcium;Calcium Signaling;care costs;Caring;Cell Death;cell injury;Cell Survival;Cells;Cellular Stress;Central Nervous System Diseases;Chromosome 6;Clinical;cost;Data;Development;disability;Disease;Disease susceptibility;DNA Maintenance;DNA Repair;DNA Repair Gene;DNA Repair Inhibition;Double-Stranded RNA;Drug Targeting;ds-DNA;expectation;Experimental Autoimmune Encephalomyelitis;Genes;Genetic Transcription;Goals;Health;Human;Immune;immune activation;Immune signaling;Individual;individual variation;Induced pluripotent stem cell derived human neuron;Inflammation;Inflammatory;Inflammatory Response;Injury;innate immune mechanisms;interdisciplinary approach;Interferon Type I;Introns;Laboratories;Lesion;Link;Long term disability;Macrophage;Maintenance;Mediating;MHC Class I Genes;Microglia;Mitochondria;Modeling;Molecular;mouse model;Multiple Sclerosis;multiple sclerosis patient;Mus;Myeloid Cells;Nervous System Disorder;Neurological disability;Neurons;novel;novel therapeutic intervention;Nuclear;Outcome;Pathway interactions;Patients;Pattern Recognition;Pharmaceutical Preparations;Predisposition;prevent;Prevention;Production;protein expression;Protein phosphatase;Proteins;Publishing;racial population;Recovery;Regulation;Research;Resolution;response;Risk;RNA Processing;RNA Splicing;Sampling;Services;Severities;Severity of illness;Signal Pathway;Signal Transduction;Sodium Channel;Spinal Cord;Stimulus;Stroke;Testing;tissue injury;tissue repair;trafficking;Transcript;Translations;Traumatic Brain Injury;treatment strategy;Variant;Veterans;Viral Genes;voltage;Work;young adult

PROJECT_TITLE: Regulation of susceptibility and severity of inflammatory diseases of the central nervous system by novel innate immune signaling pathways in human myeloid cells


ORG_CITY: BUFFALO

ORG_NAME: VA WESTERN NEW YORK HEALTHCARE SYSTEM

ORG_STATE: NY

PHR: This project has high relevance to Veterans health. Acinetobacter baumannii is an increasingly important healthcare associated pathogen that infects active military and veteran populations in both the acute and long- term care settings. It is frequently extensively drug resistant (XDR) making treatment difficult. Infections due to XDR strains result in increased cost, morbidity, and mortality. Previous work by our group identified several potential new antimicrobial targets in A. baumannii, one of which was the penicillin binding protein 7/8 (PBP 7/8), the focus of this proposal. PBP 7/8 possesses many characteristics that predict its’ potential as a high value target. Given the ongoing antimicrobial crisis it was deemed important to further explore PBP 7/8 as a drug target in XDR-A. baumannnii, and to begin the process of identifying inhibitors. This proposal will set the stage for downstream optimization and pre-clinical studies with the goal of developing a new antimicrobial class active against XDR-A. baumannii.

PI_NAMEs: RUSSO, THOMAS A (contact)

PROJECT_TERMS: Abscess;Acinetobacter baumannii;Active Sites;Acute;Affect;Anti-Bacterial Agents;anti-microbial drug;antimicrobial;Antimicrobial Resistance;Ascites;assay development;Attention;Bacillus;bactericide;Binding;Biological Assay;capsule;Carbapenems;Ceftazidime;Cells;Cellular Structures;Characteristics;Complement;cost;Cytolysis;Data;Development;drug development;Drug resistance;drug resistant pathogen;Drug Targeting;Elements;Endopeptidases;Escherichia coli;ESKAPE pathogens;extensive drug resistance;Generations;Goals;Growth;Health;Health Care Costs;Healthcare;high throughput screening;Homologous Gene;Host Defense;Human;In Vitro;in vivo;Incidence;Infection;inhibitor;Insecta;insight;Laboratories;Lactams;Location;Long-Term Care;Mediating;Meropenem;Methods;Microbial Biofilms;Military Personnel;military veteran;Modeling;molecular mass;Molecular Weight;Monoclonal Antibodies;Monoclonal Antibody Therapy;Morbidity - disease rate;mortality;Muramidase;novel strategies;pathogen;Pathogenicity;Penicillin Binding Protein 2;Penicillin Binding Protein 4;Penicillin-Binding Proteins;Penicillins;Peptidoglycan;Performance;periplasm;Permeability;Pneumonia;Population;preclinical study;Predisposition;Prevention approach;Process;Production;Rattus;Reporting;Research Personnel;Resistance;Resistance development;resistant strain;Salmonella;Serum;small molecule;small molecule libraries;Specificity;Structure;Subcutaneous abscess;Tazobactam;Testing;Tobramycin;tool;trait;transposon sequencing;Veterans;Work

PROJECT_TITLE: Determining the value of PBP 7/8 as an antimicrobial target for XDR-A. baumannnii


ADMINISTERING_IC: DC

ED_INST_TYPE: SCHOOLS OF ARTS AND SCIENCES

IC_NAME: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS

ORG_CITY: MINNEAPOLIS

ORG_DEPT: PSYCHOLOGY

ORG_NAME: UNIVERSITY OF MINNESOTA

ORG_STATE: MN

PHR: PROJECT NARRATIVE Frequency modulations are crucial to our ability to communicate via speech and music. This research will provide insights into how frequency modulation is represented in the normal-hearing human auditory system across the adult lifespan. These findings will be an important first step towards revealing how the coding of frequency modulation changes with both age and hearing loss and will help guide future interventions to improve communications for people with hearing difficulties.

PI_NAMEs: WHITEFORD, KELLY L (contact)

PROGRAM_OFFICER_NAME: KING, KELLY ANNE

PROJECT_TITLE: Neural and Perceptual Mechanisms for Coding Frequency Modulation

STUDY_SECTION: CDRC

STUDY_SECTION_NAME: Communication Disorders Review Committee[CDRC]


ORG_CITY: SALT LAKE CITY

ORG_NAME: VA SALT LAKE CITY HEALTHCARE SYSTEM

ORG_STATE: UT

PHR: Asthma is one of the major airway inflammatory diseases impacting millions worldwide. Sex disparities exist in asthma in the general population, but more so in the Veteran population. In particular, female Veterans have a higher incidence of acute and chronic airway exacerbations in comparison to male Veterans. The proposed research is relevant to the Veterans Affairs’ mission because the number of female Veterans has continuously grown in the past 3 decades and with the growth of this population, distinct healthcare issues have arisen. The current proposal is aimed at identifying sex-specific immunologic approaches focused on innate immune lymphoid cells to limit the burden of asthma in the distinct, male and female Veteran populations.

PI_NAMEs: WARREN, KRISTI J (contact)

PROJECT_TERMS: Acute;Adult women;Airway Disease;airway epithelium;airway hyperresponsiveness;Allergens;Allergic;allergic airway disease;Allergic inflammation;Asthma;asthmatic;asthmatic airway;Attention;B-Lymphocytes;biological sex;Blood;career;Caring;CC chemokine receptor 4;CCL11 gene;CCL17 gene;CCL22 gene;CCL3 gene;Cell Proliferation;Cell Separation;Cell Survival;Cells;Cessation of life;chemokine;chemokine receptor;Chronic;chronic respiratory disease;Clinical;Communities;Complex;cytokine;Data;Dendritic Cells;design;Diagnosis;Disease;Disparity;Doctor of Philosophy;Environment;eosinophil;Estrogens;Event;Extrinsic asthma;Feedback;Female;Functional disorder;Funding;Future;General Population;Goals;Gonadal Steroid Hormones;Health;Healthcare;Healthcare Systems;Hormones;Hospitals;Human;human data;Hypersensitivity;IL7 gene;Immune;Immunobiology;Immunologics;in vivo;Incidence;individualized medicine;Inflammation;Inflammatory;Inflammatory Response;Innate Immune System;interest;Interleukin 2 Receptor Gamma;Interleukin-13;Interleukin-2;Interleukin-5;Iowa;Link;Lung;Lymphoid Cell;Macrophage;male;Mediating;Mediator;Medical;Medical center;Medical Research;men;Mentorship;Middle Eastern;migration;military veteran;Mission;Mus;Nebraska;NF-kappa B;novel;Ovarian;Ovarian hormone;Ovariectomy;Pathology;Pathway interactions;personalized therapeutic;PIK3CG gene;Pilot Projects;Play;Population;Population Growth;post-doctoral training;Predisposition;Production;Progesterone;Proliferating;Prostaglandin D2;recruit;Reporting;Research;Research Personnel;Research Proposals;respiratory;respiratory challenge;Respiratory Signs and Symptoms;response;Role;Science;Scientist;Severity of illness;sex;Sex Differences;sex disparity;Signal Pathway;Signal Transduction;Source;Symptoms;synergism;Testosterone;Therapeutic Studies;Translating;United States Department of Veterans Affairs;Universities;Utah;Veterans;Woman;Work

PROJECT_TITLE: Migration and signaling in ILC2 in asthma:  Male and female differences


PHR: Dr. Lau is a key and contributing member of the San Francisco VA Health Care System. He is a world authority in the genetics of the male-specific Y chromosome and an expert in molecular genetics and animal modeling of human diseases. He has developed a vigorous research program to investigate the contributions of the male- specific portion of the human genome (genetic materials) to gender disparities in various cancers and diseases. He correlates the laboratory results to the clinical features and outcomes and identifies biomarkers for precise diagnosis and prognosis in prostate and liver cancers, cardiovascular and neurodegenerative diseases. He establishes animal models for various cancer and human diseases, affecting many of our Veterans. His studies have shed critical insights on the disease mechanisms and provided therapeutic targets for development of effective treatment plans for human cancers and diseases. His research has provided significant translational potentials to improve the healthcare of our Veterans in the twenty-first century.

PI_NAMEs: LAU, YUN-FAI CHRIS  (contact)

PROJECT_TERMS: Acceleration;Affect;Alzheimer's Disease;Animal Model;authority;Award;Bacteria;Binding;Bioinformatics;Biological Markers;Biology;biomarker identification;California;Cardiovascular Diseases;Cardiovascular system;career;CDC2 gene;Cell Proliferation;Cells;Chromosome Mapping;chromosome Y loss;Chromosomes;Chromosomes, Human, Y;Clinical;Clinical Management;Cloning;Cloning Vectors;Code;Collaborations;Cyclin B;Databases;design;Development;Diagnosis;differential expression;Disease;Disease Progression;DNA Library;dosage;Ectopic Expression;Educational workshop;effective therapy;Elderly man;Embryo;Epithelial Cells;Equipment;experimental study;Family;Feedback;Foundations;Funding;gender disparity;Gene Activation;Genes;Genetic;Genetic Materials;Genetic Models;Genetic Predisposition to Disease;Genetic Transcription;Genome;Genomic Instability;Genomics;germline stem cells;Gonadal structure;Gonadoblastoma;Health;health care delivery;Health Services Research;Healthcare;Healthcare Systems;Hepatocyte;Histones;Homologous Gene;Hormone Receptor;Human;human disease;Human Genome;human model;Immunologic Surveillance;Impairment;improved;Incidence;Inhibition of Cell Proliferation;insight;interest;International;Journals;Knowledge;Laboratories;Laboratory Finding;Link;lung development;Lysine;male;male sex hormones;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant neoplasm of prostate;Malignant Neoplasms;Mammalian Cell;Maps;Mediating;Medical;member;Methods;Molecular;Molecular Genetics;mortality;mosaic loss;mouse model;Myocardial Infarction;Nature;Neurodegenerative Disorders;neurogenesis;new technology;next generation sequencing;non-alcoholic fatty liver disease;older men;Oncogenes;Oncogenic;Outcome;peripheral blood;Pharmaceutical Preparations;Physiology;Pilot Projects;Population;postnatal;precision medicine;Predisposition;professor;Prognosis;programs;Property;Prostate;Proteins;Proto-Oncogenes;Publishing;Recombinant DNA;Reporting;Research;research and development;Research Personnel;Risk;Role;San Francisco;Science;Scientist;Screening procedure;Series;sex;Sex Chromosomes;sex determination;Sex Differences;sexual dimorphism;Signal Pathway;Somatic Cell;sry Genes;Stem Cell Factor;Stimulation of Cell Proliferation;System;targeted treatment;Techniques;Technology;Testing;Testis;Therapeutic;therapeutic target;Time;Tissues;TK Gene;tool;Transactivation;transcription factor;Transgenes;Transgenic Mice;translational applications;translational potential;Treatment outcome;treatment planning;treatment response;TSPY1 gene;Tumor Suppressor Proteins;tumorigenesis;United States National Academy of Sciences;Universities;Validation;Variant;Veterans;Work;X Chromosome;Y Chromosome


PHR: There is a high prevalence of mild traumatic brain injuries (mTBIs) within Operation Enduring Freedom and Operation Iraqi Freedom Veterans. There is evidence that mTBI can result in impaired binaural processing mechanisms responsible for the perception of speech in noise. Presently, little is known about how mTBI can impact bottom-up sensory or top-down cognitive mechanisms responsible for speech understanding complex auditory environments. This gap in knowledge contributes to the lack of evidence-based assessment and reha- bilitation protocols for clinicians working with this unique population. Our approach is to identify the effects of mTBI on sensory and cognitive neural mechanisms using a comprehensive electrophysiological test battery. This work will provide knowledge about the neurophysiological effects of mTBI on binaural auditory processing and speech perception, which will drive future research on the development of individualized auditory assess- ment and rehabilitation methods for these individuals.

PI_NAMEs: KOERNER, TESS  (contact)

PROJECT_TERMS: Affect;Athletic Injuries;Attention;attentional modulation;Auditory;auditory processing;behavior measurement;behavior prediction;Behavioral;Binaural;blast exposure;Brain Injuries;Central Nervous System;Clinical;Clinical assessments;clinical development;clinical diagnosis;Clinical Protocols;Clinical Treatment;Code;Cognitive;cognitive process;comparison control;Complex;Cues;design;Detection;Development;Diagnosis;Electrophysiology (science);Environment;evidence base;experience;falls;Freedom;Future;Goals;Hearing;Hearing problem;High Prevalence;Impairment;improved;Individual;Knowledge;Lead;Measures;Methods;mild traumatic brain injury;Modeling;neural;neuromechanism;neurophysiology;Noise;normal hearing;operation;Outcome;Outcomes Research;Participant;patient population;Patient Self-Report;Patients;Pattern;Performance;Peripheral;Population;predictive modeling;Process;programs;Protocols documentation;Recording of previous events;Rehabilitation therapy;Reporting;Research;Research Proposals;response;Sensory;Sensory Aids;Signal Transduction;sound;source localization;Speech;speech in noise;Speech Perception;stem;Stimulus;Stream;Structure;Testing;tool;Training Programs;treatment strategy;vehicular accident;Veterans;Work

PROJECT_TITLE: Effects of Non-Blast mTBI on Binaural Processing and Speech Understanding in Noise

STUDY_SECTION_NAME: Career Development Program - Panel II[RRD9]


ORG_CITY: MATHER

ORG_NAME: VA NORTHERN CALIFORNIA HEALTH CARE SYS

PHR: Many patients, especially the elderly, tolerate chemotherapy poorly--a finding that has been demonstrated to limit efficacy and the possibility of cure. The development of less toxic treatments or non-toxic therapies that make standard therapy work better is very relevant. This proposal lays the groundwork for development of new, effective, inexpensive, and less-toxic treatment approaches for lymphoma, lung cancer and other malignancies that are commonly found in veterans. Approximately 250,000 people in the USA have NHL and over 400,000 with lung cancer. While there have been advances in treatment for both diseases the vast majority still succumbs to their diseases. The fastest growing segment of the population acquiring this disease is elderly males (a substantial segment of the VA patient population) that tolerate chemotherapy poorly. Novel more effective, less toxic and inexpensive agents are needed. Given this, and the fact that NHL is an agent orange-associated malignancy, the impact on veterans is substantial.

PI_NAMEs: TUSCANO, JOSEPH M (contact)

PROJECT_TERMS: Adult;Affect;agent orange;Alternative Medicine;American;Animal Model;Animals;anticancer activity;aqueous;Award;Biochemical;Biological Assay;Biology;Cancer cell line;Cancer Etiology;cancer immunotherapy;cancer therapy;candidate identification;Canis familiaris;cell killing;Cessation of life;checkpoint inhibition;chemotherapy;Clinical Data;Clinical Research;Clinical Trials;clinically actionable;Collaborations;Column Chromatography;commercialization;Complementary Health;Complex;Country;cytotoxic;cytotoxicity;Data;Development;dietary supplements;Disease;Dose;Drug Combinations;drug development;Drug Prescriptions;Elderly;Environmental Risk Factor;experience;experimental study;exposed human population;Exposure to;Expression Profiling;Fermentation;follow-up;Fractionation;Germ;Goals;Healthcare;Hematologic Neoplasms;Human;human disease;human model;Immune;Immunity;Immunologics;immunoregulation;Immunotherapy;In Vitro;in vitro activity;in vivo;in vivo Model;Interferon Type II;Laboratory mice;Large Intestine Carcinoma;Legal patent;Ligands;Lymphoma;male;Malignant neoplasm of lung;Malignant Neoplasms;Mediating;Medicine;Melanoma;men;Monoclonal Antibodies;mouse model;multidisciplinary;Names;Natural Killer Cells;Natural Products;Natural Source;neoplastic cell;Non-Hodgkin's Lymphoma;non-Hodgkin's lymphoma patients;Non-Small-Cell Lung Carcinoma;novel;Oncologist;Oncology;patient population;Patients;Peptides;Persons;Phase;Phase II Clinical Trials;Population;pre-clinical;Pre-Clinical Model;pre-clinical research;Production;Property;Protein Array;Proteins;Publishing;receptor;Regimen;Relapse;Reporting;Research;Resources;response;rituximab;Role;Running;Saccharomyces cerevisiae;Squamous cell carcinoma;standard of care;Survival Rate;Techniques;Therapeutic;Time;Toxic effect;Translating;translational scientist;tumor;tumor eradication;United States;Veterans;Veterinary Medicine;Veterinary Schools;Wheat;Woman;Work

PROJECT_TITLE: Fermented wheat germ proteins;mechanistic, immunologic and pre-clinical canine studies


ADMINISTERING_IC: NS

FUNDING_MECHANISM: OTHER RESEARCH-RELATED

IC_NAME: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

NIH_SPENDING_CATS: Bioengineering;Neurosciences

ORG_CITY: BOZEMAN

ORG_DEPT: ANATOMY/CELL BIOLOGY

ORG_NAME: MONTANA STATE UNIVERSITY - BOZEMAN

ORG_STATE: MT

PHR: Project Narrative The BRAIN initiative has driven many laboratories to create new genetically encoded fluorescent probes and biosensors for multiphoton imaging of brain. To characterize their multiphoton properties we created a special Resource for Multiphoton Characterization of Genetically-Encoded Probes that is supported by NIH/NINDS. Over the previous funding period our Resource was used by 17 different investigators and if the grant renewed, this number will increase to 30 labs by the end of the 5th year of the next cycle.

PI_NAMEs: DROBIZHEV, MIKHAIL  (contact)

PROGRAM_OFFICER_NAME: TRZCINSKI, NATALIE KATHERINE

PROJECT_TERMS: absorption;Biliverdine;Binding;Biosensor;Brain;Brain imaging;BRAIN initiative;Cells;chromophore;Communities;coral;cost;Custom;Cyclic AMP;Educational workshop;Equilibrium;Equipment;Escherichia coli;Exhibits;Extinction;extracellular;Fluorescence;Fluorescent Probes;Funding;Goals;Grant;Harvest;improved;Jellyfish;Kinetics;Knowledge;Label;Laboratories;Laser Scanning Microscopy;Lasers;Ligands;Measurement;Measures;Methods;Microscope;Microscopy;Mission;Molecular;multi-photon;multiphoton imaging;National Institute of Neurological Disorders and Stroke;Nature;neural network;neuronal circuitry;Neurotransmitters;Optics;Photons;Phytochrome;Property;Proteins;protonation;Publications;quantum;Research;Research Personnel;Resources;response;Second Messenger Systems;sensor;Signal Transduction;tool;Training;two-photon;United States National Institutes of Health;virtual;web site

STUDY_SECTION_NAME: Special Emphasis Panel[ZNS1 SRB-S (14)]


ADMINISTERING_IC: CA

ED_INST_TYPE: SCHOOLS OF MEDICINE

FUNDING_MECHANISM: TRAINING, INDIVIDUAL

IC_NAME: NATIONAL CANCER INSTITUTE

NIH_SPENDING_CATS: Cancer;Genetics;Prevention;Skin Cancer

ORG_DEPT: INTERNAL MEDICINE/MEDICINE

ORG_NAME: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO

PHR: Project Narrative Healthy cells with mutations associated to tumor growth do not all become tumors. In the proposed research, the mechanisms connecting oncogenic Ras to microenvironmental selection pressures which promote neoplastic growth will be identified. Understanding promotion, or non-mutagenic, processes that are involved in the evolutionary selection of mutant cells to become tumorigenic will inform novel strategies for early detection and therapeutic prevention of deadly Ras-dependent cancers.

PI_NAMEs: BOLLAM, SAUMYA REDDY (contact)

PROGRAM_OFFICER_NAME: ADAMS, GREGORY

PROJECT_TERMS: Acetates;Address;Anthracenes;California;Cancer Biology;cancer genetics;Candidate Disease Gene;candidate identification;carcinogenesis;carcinogenicity;Carcinoma;career;Cell Cycle;Cell Physiology;Cell surface;cell type;Cells;chemical carcinogenesis;Chemical Models;Chronic;Comprehensive Cancer Center;Computational Biology;Data;Data Analyses;Dermal;Development;dimethylbenzanthracene;Dorsal;Early Diagnosis;Environment;Environmental Exposure;Epithelial Cells;Exhibits;experience;extracellular;Family;Gene Expression;Gene set enrichment analysis;Genes;Genetic;Germ Lines;Goals;graduate student;Growth;Histologic;Hour;Human;human tissue;immune cell infiltrate;immunoregulation;Infiltration;Inflammation;Inflammatory;inflammatory milieu;innovation;insight;Institution;Investigation;Knowledge;KRAS oncogenesis;Ligands;Link;Macrophage;Malignant Neoplasms;Measures;Mediating;Mediator;Mentors;Modeling;Molecular;mouse model;Mus;Mutagens;mutant;Mutate;Mutation;Neoplasms;novel;novel strategies;Oncogenic;Pathway Analysis;permissiveness;Play;Population;population based;pressure;Prevention;Prevention strategy;Process;programs;Proliferating;promoter;receptor;Regimen;Research;Resolution;Resources;response;Role;San Francisco;Science;Signal Transduction;single-cell RNA sequencing;Skin;Skin Cancer;skin squamous cell carcinoma;Students;Tetradecanoylphorbol Acetate;theories;Therapeutic;Time;Tissues;tool;Training;transcriptome;tumor;tumor growth;Tumor Promotion;tumorigenesis;tumorigenic;Universities;Work;wound healing

PROJECT_TITLE: Selection of oncogenic Ras mutations through tumor promotion mechanisms


ORG_CITY: BRONX

ORG_NAME: JAMES J PETERS VA  MEDICAL CENTER

PHR: Project Narrative Diabetic kidney disease (DKD) and focal segmental glomerulosclerosis (FSGS) are common cause of end- stage renal disease in the US and in our veterans. However current regimen provides only partial therapeutic effects and the incidence and prevalence of these diseases remains high, suggesting that the key pathogenic mechanisms driving DKD progression are not adequately inhibited by current treatments. Therefore, better understanding of mechanisms that drive the disease progression is urgently required and therefore we could develop novel therapeutic measures for DKD and FSGS patients. The proposed studies may lead to the discovery of a new class of drugs to treat these two diseases.

PI_NAMEs: HE, JOHN CIJIANG (contact)

PROJECT_TERMS: Address;Adriamycin PFS;Affinity;Agonist;AIDS-Associated Nephropathy;Albuminuria;Antiinflammatory Effect;Apoptosis;Apoptotic;Attenuated;Automobile Driving;Binding;Biological;Biological Availability;Biology;Blood coagulation;Cell Survival;Coagulation Process;Code;Data;design;Development;diabetic;Diabetic mouse;Diabetic Nephropathy;diabetic rat;Disease;Disease Progression;End stage renal failure;Family;Focal and Segmental Glomerulosclerosis;Funding;glomerular filtration;Human;improved;In Vitro;in vivo;Incidence;Individual;Inflammation;Inhibition of NF-KB activation;Injections;Injury;Injury to Kidney;insight;Kidney;Kidney Diseases;knock-down;Knock-out;Knockout Mice;Larva;Lead;Ligands;Measures;Mediating;Messenger RNA;mRNA Expression;Mus;novel;novel drug class;novel therapeutics;Paper;Pathogenicity;Pathway interactions;Patients;Pharmaceutical Preparations;Pharmacotherapy;Phosphorylation;podocyte;Prevalence;Preventive;Process;protective effect;protective pathway;Protein Overexpression;Protein S;Proteins;Proteomics;Proto-Oncogene Proteins c-akt;receptor;Receptor Protein-Tyrosine Kinases;Recombinant adeno-associated virus (rAAV);Regimen;Regulation;Renal glomerular disease;Role;Signal Transduction;Solubility;Specificity;Structure;Structure-Activity Relationship;Testing;Therapeutic;Therapeutic Effect;Treatment-related toxicity;Veterans;Wild Type Mouse;Zebrafish

PROJECT_TITLE: Role of Protein S in early Diabetic Kidney Disease


ORG_CITY: DAYTON

ORG_NAME: DAYTON VA MEDICAL CENTER

ORG_STATE: OH

PHR: PROJECT NARRATIVE The primary long-term goal of our research is to characterize the role of the lipid mediator Platelet-activating factor (PAF) in ultraviolet B (UVB) radiation-induced immunosuppression which is responsible for skin cancers. We have shown that UVB generates subcellular microvesicle particles (MVP) which are not only dependent upon PAF, they appear to carry PAF agonists from the epidermal keratinocytes. These studies will define the mechanisms by which UVB generates MVP and define if this novel pathway can be exploited pharmacologically to block UVB-induced immunosuppression.

PI_NAMEs: TRAVERS, JEFFREY B. (contact)

PROJECT_TERMS: acid sphingomyelinase;Actinic keratosis;Address;Agonist;Antioxidants;Area;Binding;Carcinogens;Cell Line;Cells;chemotherapy;cigarette smoke;Clinic;Cytoplasm;Data;Dermatology;design;Diagnosis;Dose;environmental agent;environmental stressor;Enzyme Inhibition;Enzymes;Epidermis;Epithelial Cells;Event;Fever;Financial Hardship;Generations;Genetic;genetic approach;Goals;Grant;Healthcare Systems;Human;Immune response;Immunosuppression;Immunosuppressive Agents;In Vitro;in vivo;Incidence;indexing;Individual;inhibitor;Ionizing radiation;keratinocyte;Knock-out;Knockout Mice;Knowledge;Laboratories;Link;lipid mediator;mast cell;Mediating;Melanoma;Melanoma Tumor;Membrane;Metabolic;microvesicles;Military Personnel;military veteran;Modeling;Morbidity - disease rate;Mus;Mutagens;Neoplasms;neoplastic cell;novel;Nuclear;Null Lymphocytes;Outcome;oxidized lipid;particle;Pathway interactions;Penetration;pharmacologic;Photobiology;Physiological;Platelet Activating Factor;platelet activating factor receptor;Play;premalignant;Process;Production;Productivity;PUVA Photochemotherapy;Radiation therapy;Reaction;Reactive Oxygen Species;Receptor Signaling;Regulatory T-Lymphocyte;Reporting;Research;response;Role;Running;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Skin;Skin Cancer;Skin Carcinoma;Skin Neoplasms;Source;Stimulus;stressor;Testing;tool;Transfer Factor;tumor progression;Tumor Promotion;Ultraviolet B Radiation;Ultraviolet Rays;UV induced;UV Radiation Exposure;UVB induced;Vesicle;Veterans;Vitamin D;Work;XPA gene

PROJECT_TITLE: Oxidized Lipids and UV Immunosuppression


ORG_CITY: NASHVILLE

ORG_NAME: VETERANS HEALTH ADMINISTRATION

ORG_STATE: TN

PHR: Regulation of Innate Immunity and Inflammation Through Nuclear Reprogramming This project is focused on the mechanistic analysis of the unprecedented enhancement of innate immunity- mediated clearance of bacteria in the lungs, spleen, and blood by a new class of cell-penetrating peptides. These anti-inflammatory peptides selectively target proinflammatory and metabolic nuclear transport pathways. We will also decode both the mechanism of the inflammatory and metabolic injury to multiple organs and increased survival in septic shock. We anticipate that this project will unravel the new genomic and immunometabolic mechanisms of this novel intracellular immunotherapy intended to be combined with antimicrobials. Thus, our innovative anti-inflammatory peptides, coupled with antimicrobials, will pave the way for the improved treatment of severe infections evolving into septic shock in wounded soldiers, Veterans, and the civilian population, thereby reducing the incidence, mortality, and post-septic shock sequelae (such as cognitive decline) in survivors.

PI_NAMEs: HAWIGER, JACK J (contact)

PROJECT_TERMS: Age;Anti-Bacterial Agents;Anti-Inflammatory Agents;anti-microbial drug;Antibiotics;antimicrobial;Bacteria;Bacterial Infections;Binding;Binding Proteins;Blood;blood glucose regulation;Brain;carbohydrate transport;Carbohydrates;Carnitine;Cell Nucleus;Cells;Cholesterol;Clinical Trials;clinically relevant;Complex;Coupled;Death Rate;design;Elements;Endothelial Cells;Endotoxins;Esters;Fatty Acids;Gene Expression;Genes;Genetic Transcription;Genome;genomic data;Genomics;Glucose;glycogenolysis;Goals;Gram-Negative Bacteria;Heart;Hereditary Disease;Human;Hyperglycemia;Hyperlipidemia;Hypersensitivity;Hypertriglyceridemia;Hypotension;Immune;Immunotherapy;Impaired cognition;Importins;improved;Incidence;Individual;Infection;Inflammation;Inflammation Mediators;Inflammatory;Injury;innovation;Interleukin-1 beta;Interleukin-6;Kidney;Laboratories;Link;lipid biosynthesis;Lipopolysaccharides;Liver;Lung;Mediating;Metabolic;Metabolic Diseases;Metabolic syndrome;microbial;Microcirculation;Modeling;Monitor;mortality;multiorgan damage;Multiple Organ Failure;Mus;Natural Immunity;novel;Nuclear Import;Nuclear Pore Complex;nuclear reprogramming;nucleocytoplasmic transport;Organ;Outcome;Pathway interactions;Patients;Penetration;Peptides;Peritonitis;Platelet Activation;Population;prevent;Production;programs;protein transport;Proteins;recurrent infection;Regulation;Regulatory Element;Reporting;Research;response;Sepsis;Septic Shock;Shock;Signal Pathway;Spleen;Sterols;Stress;Survival Rate;Survivors;Testing;Thrombocytopenia;Thrombus;Tissues;TNF gene;transcription factor;Treatment Protocols;Triglycerides;Vascular Endothelial Cell;Vascular Endothelium;Veterans;Virulence Factors;western diet;wounded soldier


ORG_CITY: ALBUQUERQUE

ORG_NAME: ALBUQUERQUE VA MEDICAL CENTER

ORG_STATE: NM

PHR: NARRATIVE The overall goal of the proposed Merit renewal studies is to improve management of chronic nerve injury pain suffered by many veterans after blast, vehicular accident, and other combat injuries. Chronic head and neck pain are chief complaints of approximately 772,000 of the 2.5 million military personnel deployed since 2001 seeking care in the VA health care system. A clinically relevant experimental model of chronic pain is used to provide information not attainable with acute models including anxiety and depression measures that can accompany chronic pain. The central pain generator identified in the previous grant period driving intense activation of the nervous system during chronic pain also drives the appearance of cellular oxidative stress and damage proteins. This indicates restorative processes that protect cellular function are compromised in the pain processing circuitry. Proposed studies will test efficacy of oxidative stress inhibitors and enhancement of cellular protection mechanisms as means to limit effects of chronic pain.

PI_NAMEs: WESTLUND-HIGH, KARIN N. (contact)

PROJECT_TERMS: Ablation;Acute;Acute Pain;Affect;Afferent Neurons;American;Analgesics;Animals;antagonist;Anxiety;anxiety-related behavior;Appearance;Automobile Driving;Autophagocytosis;Behavior;Behavioral;Behavioral Assay;Bioenergetics;Biological Markers;Brain;brain circuitry;Brain region;care seeking;Cathepsins B;Cell Physiology;Cells;Cellular Stress;Central Nervous System;central pain;Chronic;chronic constriction injury;chronic neuropathic pain;chronic pain;chronic pain management;Clinical;clinically relevant;combat injury;Confocal Microscopy;constriction;Data;design;Development;Doxazosin;efficacy evaluation;efficacy testing;Emotional;endoplasmic reticulum stress;Enhancers;Experimental Models;Fluorescent Probes;follow-up;Functional disorder;Functional Magnetic Resonance Imaging;Funding;Future;Gene Expression Profile;Goals;Grant;Head and neck structure;Healthcare Systems;Heat shock proteins;Histologic;histological studies;Homeostasis;Hypersensitivity;Image;Immunohistochemistry;improved;in vivo;Inflammatory;inhibitor;Injury;interest;Knowledge;Literature;Magnetic Resonance Imaging;Manganese;Measures;Mechanics;Mental Depression;Military Personnel;misfolded protein;Mitochondria;Modeling;Mus;Neck Pain;Nerve;nerve injury;nerve supply;Nervous System;neural;Neurons;neuropathology;non-opioid analgesic;noradrenergic;Opioid;opioid overdose;Orofacial Pain;Outcome;oxidative damage;Oxidative Stress;Pain;pain behavior;pain chronification;pain model;pain processing;pain reduction;painful neuropathy;Patients;Peripheral Nervous System;pharmacologic;Pharmacologic Substance;Post-Traumatic Stress Disorders;Prazosin;preclinical efficacy;Process;Progress Reports;promoter;Prosencephalon;protein expression;Proteins;Rattus;receptor;Receptor Signaling;Reporting;RNA;Rodent;Signal Pathway;Signal Transduction;Sirolimus;suicide rate;Testing;Therapeutic;Time;transcriptome sequencing;Treatment Efficacy;treatment response;Trigeminal System;Validation;vehicular accident;Veterans;Visualization;Western Blotting

PROJECT_TITLE: Modulating Pain Generators of Chronic Trigeminal Neuropathic Pain


ORG_CITY: SALISBURY

ORG_NAME: W G HEFNER VA MEDICAL CENTER

ORG_STATE: NC

PHR: PROJECT NARRATIVE  We have studied a novel and easily modifiable risk factor for diabetes, namely high tissue iron levels, that we have shown impairs insulin secretion, one of the hallmarks of type 2 diabetes. More recent work has indicated that many of these effects are mediated by two pathways, the so-called hypoxia sensing pathway and a nutrient sensing pathway that modifies proteins with a sugar, GlcNAc. In mouse models and in humans, we have shown that these pathways interact with iron to determine insulin secretion and production of a major regulator of metabolism, leptin. Major changes in blood glucose levels can be achieved by manipulating one or both. We therefore propose studies to further define these effects and their molecular mechanisms, focusing on a pathway that we have found to integrate iron status in other tissues. Our goal is to define potential new targets for diabetes therapy, and define personalized “ideal” iron levels for diabetes prevention and treatment. !

PI_NAMEs: MCCLAIN, DONALD A. (contact)

PROJECT_TERMS: adiponectin;Adipose tissue;Affect;Altitude;Beta Cell;Blood Donations;Blood Glucose;blood glucose regulation;Cell Physiology;Cell Respiration;Cells;Complex;CREB1 gene;Data;Dependence;detection of nutrient;Diabetes Mellitus;diabetes mellitus therapy;Diabetes prevention;Diet;Dietary Iron;Elements;Enzymes;EP300 gene;Exposure to;Fatty acid glycerol esters;FOXO1A gene;FRAP1 gene;Gene Activation;Genetic Transcription;Genus Hippocampus;Glucosamine;Glucose;glucose metabolism;glucose production;glycosylation;Goals;Harvest;Health;Hepatic;Hexosamines;Homeostasis;Human;human tissue;Hypoxia;Hypoxia Pathway;Impairment;Individual;Insulin;Insulin Resistance;insulin secretion;insulin sensitivity;Iron;Iron Overload;islet;Leptin;Link;Mediating;Metabolic;Metabolic Pathway;Metabolism;Mitochondria;Mixed Function Oxygenases;modifiable risk;Modification;Molecular;mouse model;Mus;Non-Insulin-Dependent Diabetes Mellitus;Normal Range;normoxia;novel;Nutrient;Nutrient availability;Obesity;oxidant stress;oxidation;Oxidation-Reduction;Oxidative Stress;Oxygen;Pathogenesis;Pathologic;Pathway interactions;personalized medicine;pharmacologic;Phosphorylation;Physiology;pleiotropism;Post-Translational Protein Processing;Production;promoter;Proteins;Proteomics;Publishing;recruit;Regulation;response;Risk Factors;Sea;sensor;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Sirtuins;sugar;System;Technology;Testing;Tissues;transcription factor;Transcriptional Regulation;transcriptome sequencing;Work

PROJECT_TITLE: Mechanism of Integrative Metabolic Regulation by Iron and Hypoxia


PHR: The apolipoprotein E gene (APOE) is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). However, the exact mechanism by which APOE contributes to AD remains elusive. Several lines of evidence suggest the presence of other AD-risk loci in close proximity to APOE gene. In our preliminary study, we observed that SNPs in an extended APOE region carry strong AD association signals independent of the APOE ε4 allele, and that multiple genes in this region have altered mRNA expression in AD postmortem brain. From this evidence, we hypothesize that multiple genes/loci in the extended APOE locus have a compound effect on AD risk. Our short-term goals are to identify APOE ε4-independent genetic loci associated with AD, and to precisely define how these loci work together to modify AD risk. Our long-term goal is to use this knowledge to develop more precise APOE locus-based prediction, prevention, and/or therapeutic strategies for AD.

PI_NAMEs: YU, CHANG-EN  (contact)

PROJECT_TERMS: Alleles;Alzheimer's Disease;Alzheimer's disease risk;Apolipoprotein E;apolipoprotein E-4;Area;Autopsy;Biological;Biological Assay;bisulfite;Brain;brain tissue;Cell Nucleus;cell type;Cells;chromatin immunoprecipitation;Chromosome Mapping;Chromosomes;Cloning;comparison control;Data;Data Set;design;Development;digital;Disease;Disease susceptibility;DNA Methylation;Enhancers;Epigenetic Process;experimental study;Flow Cytometry;Foundations;Frequencies;Gene Combinations;Gene Expression;Gene Expression Regulation;Genes;Genetic;genetic association;Genetic Diseases;genetic risk factor;Genetic Structures;Genetic Transcription;genetic variant;genome wide association study;genomic locus;Goals;Haplotypes;Heterozygote;histone modification;Human;Human Cell Line;Individual;Intervention;Knowledge;Late Onset Alzheimer Disease;Link;Mainstreaming;MicroRNAs;Molecular;Molecular Target;mRNA Expression;Neuroglia;Neurons;Pathway interactions;personalized medicine;Phase;Phenotype;Population;prevent;Prevention;promoter;Protein Isoforms;pyrosequencing;Quantitative Reverse Transcriptase PCR;Regulation;Reporter Genes;Research;Risk;risk variant;Role;Signal Transduction;Single Nucleotide Polymorphism;Site;Specificity;Structure;Testing;Therapeutic;therapeutic gene;Thinking;tool;transcription factor;Variant;Work

PROJECT_TITLE: Defining high- and low-risk APOE ÃÂµ4 haplotypes for AlzheimerÃ¢ÂÂs disease


ORG_CITY: DETROIT

ORG_NAME: JOHN D DINGELL VA MEDICAL CENTER

ORG_STATE: MI

PHR: Project Narrative This project is highly relevant to public health and the health of Gulf War Veterans because it will determine how Gulf War agents interact with the gut microbiome. This project will fill gaps in our understanding of how Gulf War agents exert their effects by altering communication along the gut–brain axis.

PI_NAMEs: ANGOA-PEREZ, MARIANA  (contact);KUHN, DONALD M

PROJECT_TERMS: 16S ribosomal RNA sequencing;Agreement;Animal Model;associated symptom;Behavior;blood-brain barrier crossing;Brain;Bromides;Characteristics;Chronic;commensal bacteria;Communication;Complex;diagnostic criteria;Diet;dietary;Dietary Intervention;Disease;Disparate;dysbiosis;Elements;Equilibrium;expectation;experimental study;fecal microbiota;Fermentation;Gulf War;Gulf War veteran;gut bacteria;gut microbiome;gut-brain axis;Health;High Fat Diet;high-fat/low-fiber diet;Institute of Medicine (U.S.);Intervention;liquid chromatography mass spectrometry;Mass Spectrum Analysis;Metabolism;metabolome;metabolomics;microbiome;microbiota;mouse model;Mus;new therapeutic target;next generation sequencing;Obesity;Outcome;Pathologic;Permethrin;Persian Gulf Syndrome;persistent symptom;Production;Psychophysiologic Disorders;Public Health;pyridostigmine;Reporting;Risk Factors;Serum;small molecule;Symptoms;Testing;Time;Volatile Fatty Acids;War;western diet

PROJECT_TITLE: Gulf War Veterans' Illness: Symptom Chronicity via Interactions of Diet andLifestyle Risk Factors with the Gut Microbiome


ORG_CITY: PALO ALTO

ORG_NAME: VETERANS ADMIN PALO ALTO HEALTH CARE SYS

PHR: As the sixth most common cancer in the U.S., bladder cancer is a major health burden for veterans. Veterans are at a higher risk for bladder cancer due to increased exposures to risk factors including tobacco use and service- related chemical exposure. There are significant unmet diagnostic needs for bladder cancer across all stages. Particularly for patients with early stage disease, current diagnostic approaches are either invasive (e.g. cystoscopy) or lack sensitivity (e.g. urine cytology). We propose to develop non-invasive molecular diagnostics based on urinary biomarkers that will lead to more effective and personalized therapeutic strategies for patients with localized bladder cancer. Successful completion of the studies proposed here will serve as a foundation for incorporating urine-based biomarkers in bladder cancer surveillance and into prospective clinical trials to assess therapeutic interventions, with the long-term goal to reduce surveillance-related morbidity and improve outcomes for veterans with bladder cancer.

PI_NAMEs: LIAO, JOSEPH C (contact)

PROJECT_TERMS: Adult;Afghanistan;agent orange;Aromatic Amines;Awareness;Bacillus Calmette-Guerin Therapy;BCG Live;Benign;Biological;Biological Markers;biomarker discovery;biomarker panel;Bladder;Blood;burden of illness;burn pit;Cancer Detection;Cancer Patient;cancer risk;cancer type;Cessation of life;Chemical Exposure;Clinical;clinical translation;Clinical Trials;Clinical Trials Design;Clinics and Hospitals;Collaborations;Cystoscopy;Cytology;Data;Decision Making;Development;Diagnosis;Diagnostic;Diagnostic Sensitivity;diagnostic strategy;diagnostic tool;Disease;Doctor of Philosophy;Emotional;Environmental Exposure;Epidemiologist;experience;Exposure to;falls;Foundations;General Population;Goals;Health;Health Services Accessibility;Hematuria;high risk;High-Throughput RNA Sequencing;improved;improved outcome;intravesical;Iraq;Lesion;Liquid substance;Malignant neoplasm of urinary bladder;Malignant Neoplasms;Measurement;Measures;Medical;Messenger RNA;Microfluidics;Microscopic;Modeling;Molecular;molecular diagnostics;molecular marker;Monitor;Morbidity - disease rate;non-muscle invasive bladder cancer;Nucleic Acids;Operative Surgical Procedures;Particulate;patient stratification;Patients;Performance;personalized approach;personalized medicine;personalized therapeutic;Population;Prediction of Response to Therapy;Procedures;prospective;Recording of previous events;Recurrence;Research;Research Design;Research Personnel;Residual Cancers;response;Risk;Risk Assessment;Risk Factors;risk stratification;Sampling;Scientist;screening;Screening for cancer;Services;Smoke;Smoking;Solid;Staging;Symptoms;Technology;Testing;Therapeutic Intervention;Tobacco use;tool;Translations;Transurethral Resection;treatment response;treatment strategy;tumor;Tumor-Derived;urinary;Urine;Urologic Diseases;Urologic Oncology;Urologic Surgeon;Validation;validation studies;Veterans;Vietnam

PROJECT_TITLE: Personalized assessment of bladder cancer treatment response using urinary molecular biomarkers


ORG_CITY: PITTSBURGH

ORG_STATE: PA

PHR: PROJECT NARRATIVE  Therapeutic interventions in stroke, the fifth most common cause of death and the leading cause of adult disability in the United States, are currently limited to thrombolytic therapy within a narrow time window and development of effective therapies is urgently required. The object of this application is to test our hypothesis that nitro-oleic acid (OA-NO2) functions as a novel BBB stabilizer and its activation of the PPARγ and other signaling pathways contribute to maintenance of BBB integrity and improvement of functional outcomes after ischemic stroke. The successful implementation of this proposal will eventually lead us to develop novel nitro- fatty acid-based drugs for the effective treatment of ischemic stroke.

PI_NAMEs: YIN, KEJIE  (contact)

PROJECT_TERMS: Adult;Affect;Age;Aging;Anti-Inflammatory Agents;Astrocytes;Atherosclerosis;Attenuated;Blood - brain barrier anatomy;Blood brain barrier dysfunction;Blood Preservation;Blood Proteins;blood-brain barrier disruption;Brain;brain endothelial cell;Brain Infarction;Brain Injuries;Cardiovascular system;Cause of Death;cell type;Cells;Cerebral Ischemia;cerebrovascular;Cerebrum;Coculture Techniques;Data;deprivation;Development;Diabetes Mellitus;disability;Edema;effective therapy;Endothelial Cells;Event;Extravasation;Fatty Acids;Functional disorder;functional improvement;Genes;Genetic;genetic manipulation;Glucose;Hemorrhage;Hospitalization;Human;Immune;immune cell infiltrate;Impairment;improved;In Vitro;Inflammation;Inflammation Mediators;Inflammatory Response;Injury;intravenous administration;Ischemia;Ischemic Brain Injury;Ischemic Stroke;Ligands;Macrophage;Maintenance;Mediating;Mediator;Medical;Middle Cerebral Artery Occlusion;migration;Modeling;Molecular;mRNA Expression;Mus;Myocardial Ischemia;neurobehavior;neurobehavioral;Neurologic;Neurologic Deficit;Neurologic Dysfunctions;Neurological outcome;neuron loss;neurovascular;neurovascular injury;Nitric Oxide;nitroalkene;Nitrogen Dioxide;novel;Oleic Acids;Outcome;Oxygen;Pathogenesis;Pathologic;Pathway interactions;Peripheral;Permeability;Peroxisome Proliferator-Activated Receptors;Pharmaceutical Preparations;pharmacologic;Pharmacologic Substance;Physiological;Plasma;Play;post stroke;PPAR gamma;prevent;protein expression;Publications;Reaction;Recovery;Regulation;renal ischemia;Reperfusion Injury;Reperfusion Therapy;Rodent;Role;Signal Pathway;Signal Transduction;Stroke;Survivors;Testing;Therapeutic;Therapeutic Intervention;therapeutically effective;Thrombolytic Therapy;Tight Junctions;Time;transcriptome sequencing;United States;vascular inflammation;Veterans

PROJECT_TITLE: Role of nitro-fatty acids in BBB stabilization and post-stroke neurovascular protection


ORG_CITY: CHARLESTON

ORG_NAME: RALPH H JOHNSON VA MEDICAL CENTER

ORG_STATE: SC

PHR: Alterations of mitochondrial homeostasis is one of the hallmarks of age-related macular degeneration. We have designed experiments to investigate the contribution of intracellular complement signaling in mitochondrial damage and ensuing pathology, as well as elucidate the contribution of exosomal cargo transferred to recipient cells on mitochondrial dynamics and energy production.

PI_NAMEs: ROHRER, BAERBEL  (contact)

PROJECT_TERMS: Affect;Age;Age related macular degeneration;American;Biology;Blindness;Bruch's basal membrane structure;Bystander Effect;Calcium;Caring;cell injury;Cells;Cellular Stress;Cessation of life;Choroid;Chronic;Communication;Complement;Complement 3a;Complement Activation;complement C3a receptor;Complement Inactivators;complement system;Complex;Complication;design;Development;Disease;Drusen;Elastases;Epigenetic Process;examination questions;exosome;Experimental Designs;Family suidae;Funding;Future;Gap Junctions;Genetic;geographic atrophy;Goals;Haplotypes;HDAC6 gene;Homeostasis;Hybrids;Incidence;Individual;induced pluripotent stem cell;Inflammation;Knowledge;Life;Location;Mediating;Mediator;Melanins;Membrane Potentials;Metabolic;Metabolism;Mitochondria;Mitochondrial DNA;mitochondrial dysfunction;mitochondrial membrane;mitochondrial metabolism;Molecular Abnormality;monolayer;Organelles;Oxidative Stress;Pathologic;Pathology;Photoreceptors;Population;Prevalence;Production;receptor;Receptor Signaling;Research;response;Risk;risk variant;Role;Severities;Signal Transduction;Smoking;Stress;Structure of retinal pigment epithelium;System;Testing;Therapeutic;transmission process;uptake;Veterans

PROJECT_TITLE: RPE Cell Bystander Effects Contribute to AMD Pathology


ORG_CITY: KANSAS CITY

ORG_NAME: KANSAS CITY VA MEDICAL CENTER

ORG_STATE: MO

PHR: Alzheimer's disease (AD) patients and some normal elderly appear to have deficiency of a molecule called GRK5, which is an important protein regulating many physiological processes, including memory. Low levels of GRK5 will make the neurons participating in memory function more susceptible to cell death. In this project, we propose to characterize and optimize an active pharmaceutic ingredient CN168 with already demonstrated proof-of-concept efficacy in preventing cognitive decline in GRK5-deficient mice. We will synthesize CN168 and its prodrugs and test them in animals to select the best prodrug candidates based on their pharmacokinetic properties. The selected prodrug(s) will then be tested again in the GRK5-deficient and normal animal models and make sure they are effective and safe to use before submitting an investigational new drug approval through the Food and Drug Administration.

PI_NAMEs: SUO, WILLIAM Z. (contact)

PROJECT_TERMS: acute toxicity;Address;Affect;Aging;Alzheimer disease prevention;Alzheimer's Disease;Alzheimer's disease patient;Alzheimer's disease therapeutic;Alzheimer's disease therapy;American;Amyloid beta-Protein;Animal Model;Animals;antagonist;Attention;Attenuated;Autoreceptors;Award;Axon;axonopathy;basal forebrain;Biological Availability;Brain;Cell Death;Cell membrane;cholinergic;Chronic;Clinic;Clinical Research;Clinical Trials;Cognitive deficits;Communication;Complement;Cyclic GMP;Data;Defense Mechanisms;Dementia;desensitization;Disease;Disease Progression;Dose;drug candidate;Drug Kinetics;Drug toxicity;Elderly;Ensure;Equilibrium;Etiology;Evaluation;Exhibits;Failure;Foundations;Free Radicals;Functional disorder;Future;G protein coupled receptor kinase;Genes;Goals;GRK5 gene;Health;Hippocampus;Human;Hypoxia;Impaired cognition;Impairment;improved;In Vitro;in vivo;Individual;Inflammatory;Investigational Drugs;Investigational New Drug Application;Knock-out;Lead;Life;manufacture;Memory;mild cognitive impairment;Mus;Muscarinic Acetylcholine Receptor;Nerve Degeneration;Neurodegenerative Disorders;neuron loss;Neurons;neurotoxic;New Drug Approvals;Nobel Prize;novel therapeutic intervention;old mice;Oral;Pathogenesis;Pathway interactions;Persons;Pharmaceutical Preparations;Pharmacodynamics;Pharmacologic Substance;Pharmacy (field);Physiological Processes;Plasma;Population;pre-clinical;Predisposition;presynaptic;prevent;Prodrugs;Property;Proteins;Research;Role;Running;screening;Serum;side effect;success;Synapses;System;tau-1;Testing;Therapeutic;Toxic effect;Toxicology;Toxin;Transgenic Organisms;Translations;Transportation;United States Food and Drug Administration;Wild Type Mouse;Work

PROJECT_TITLE: Optimization and preclinical characterization of anthranilamide derivatives for Alzheimer prevention


ORG_CITY: IOWA CITY

ORG_NAME: IOWA CITY VA MEDICAL CENTER

ORG_STATE: IA

PHR: The applicant's research focuses upon defining the functions of an important subset of white blood cells called lymphocytes. One type, termed B lymphocytes, produces soluble immune defense molecules called antibodies. The other, called T lymphocytes, recognizes non-self molecules on infected body cells and tumor cells, and works together with B lymphocytes to provide immune protection. However, lymphocytes can also become abnormal, and develop into human cancers. Cancers of B cells, which are relatively common, are even more frequent in Veterans than in the general population. The applicant's research team studies a regulatory protein called TRAF3 that prevents B cells from the abnormally high survival ability characteristic of cancer cells. This protein, known as a `tumor suppressor', is down-regulated in B cells as we age, and is also quite low in many B cell cancers. We are studying why and how this occurs, so the problem can be countered therapeutically. We also study additional B cell molecules that regulate their function in immunity and cancer.

PI_NAMEs: BISHOP, GAIL A. (contact)

PROJECT_TERMS: Abnormal Cell;Adaptor Signaling Protein;Age;Aging;Antibodies;Area;Autoimmunity;Award;B lymphoid malignancy;B-Cell Lymphomas;B-Cell Neoplasm;B-Lymphocytes;Basic Science;Biological;Biological Markers;Blood;c-myc Genes;cancer cell;cancer therapy;career;Cell Aging;cell killing;Cell Surface Receptors;Cell Survival;cell type;Cells;Characteristics;Chronic;Clinic;Clinical;clinical application;Clinical Trials;clinically relevant;Collaborations;Communicable Diseases;Communities;Community Participation;Development;Disease;Doctor of Philosophy;Ebola virus;Educational process of instructing;effective therapy;Ensure;Event;fighting;Funding;Future;General Population;Genes;genetic regulatory protein;Genetic Transcription;Glucose;glucose metabolism;glucose uptake;Goals;Graft Rejection;Grant Review;Health;Human;Human Herpesvirus 4;humoral immunity deficiency;Immune;Immune response;Immunity;improved;Industry;Infection;Inflammatory;inhibitor;insight;interest;Interleukin 6 Receptor;Interleukin-6;International;Intervention;Investigation;Iowa;Knowledge;Laboratories;Leadership;Learning;Leukocytes;Life;LMP1;loss of function;Lymphocyte;Lymphocyte Biology;Lymphocyte Function;Lymphoma;Malignant neoplasm of pancreas;Malignant Neoplasms;Manuscripts;Measures;Mediating;Medical;Mentors;Metabolism;military veteran;Molecular;Monoclonal Antibodies;Mouse Strains;Multiple Myeloma;Mus;Mutation;Nature;neoplastic cell;news;next generation;Nuclear Protein;Oncogenic;Oncologist;Pathogenesis;Pathway interactions;Phenotype;Phosphoric Monoester Hydrolases;Physicians;Play;Population;Post-Translational Protein Processing;Predisposition;Preparation;prevent;Process;programs;Progress Reports;protein function;Proteins;PTPN22 gene;Publications;receptor;recruit;Regulation;Research;Research Personnel;Resistance;restraint;Role;Scientific Societies;Scientist;Services;Signal Transduction;Signaling Protein;small molecule inhibitor;Source;Specialist;T-Lymphocyte;Therapeutic;TNF receptor-associated factor 3;TNFRSF5 gene;Toxin;Translating;Translations;treatment trial;tumor;Tumor Necrosis Factor Receptor;Tumor Suppressor Proteins;Universities;Veterans;Virus Diseases;Work

PROJECT_TITLE: BLRD Research Career Scientist Award Application


ORG_CITY: TAMPA

ORG_NAME: JAMES A. HALEY VA MEDICAL CENTER

ORG_STATE: FL

PHR: This application is for Research Career Scientist award for Niketa A. Patel, Ph.D., 8/8th VA, PI of active VAMR award, national peer-reviewed research support since 2005, office and laboratory in JAHVH Research Service space. Dr. Patel’s cutting-edge research supports VA mission to boost healthcare of Veterans as evidenced by continuous federal funding, high impact publications and collaborations within VA and in academia. Dr. Patel’s record demonstrates extensive service to local VA and nationally as well as at the affiliate USF which also includes teaching and mentoring graduate and medical students. Dr. Patel holds five US patents with VA asserted rights. Dr. Patel has successfully collaborated with VA clinicians and scientists which have resulted in publications and grants. Overall, Dr. Patel’s research and service to VA supports the application of a career-track for non-clinician RCS award.

PI_NAMEs: PATEL, NIKETA A. (contact)

PROJECT_TERMS: Academia;adipose derived stem cell;Adipose tissue;Affect;Afghanistan;Alternative Splicing;American soldier;Award;beneficiary;Biochemistry;Biology;Brain Injuries;Cardiovascular Diseases;career;Career Choice;career development;Caring;Cells;Chemicals;Chronic;Chronic Disease;Classification;Clinical;Code;Collaborations;combat readiness;comorbidity;Core Facility;cost;Country;Development;Disease;Doctor of Philosophy;economic cost;Educational process of instructing;Endocrine Glands;exosome;Expenditure;Florida;Functional disorder;Funding;General Population;Goals;graduate student;Grant;Guidelines;Healthcare;Human;human tissue;IACUC;In Vitro;in vivo;inhibitor;International;Iraq;Journals;Laboratories;Leadership;Legal patent;Malignant Neoplasms;Medical;Medical Students;meetings;Mentors;Metabolic Diseases;Metabolic syndrome;Metabolism;Mission;Molecular;neuroinflammation;news;Non-Insulin-Dependent Diabetes Mellitus;novel;novel therapeutics;Obesity;Overweight;Physiology;Primary Care;programs;Publications;Publishing;Quality of life;regenerative approach;Reporting;Research;research and development;Research Peer Review;Research Support;Review Committee;Rights;Risk;RNA;Rodent;Role;Scientist;Services;Signal Transduction;stem cell niche;stem cells;symposium;System;TBI treatment;Technology;Therapeutic;transcriptome sequencing;transcriptomics;Translational Research;Traumatic Brain Injury;trend;undergraduate student;United States Department of Veterans Affairs;United States National Institutes of Health;Universities;Untranslated RNA;Veterans;Veterans Hospitals;Vietnam;Work


ORG_CITY: St. Louis

ORG_NAME: ST. LOUIS VA MEDICAL CENTER

PHR: Traumatic brain injury (TBI) is both the leading cause of death and disability for active service members and the best established acquired risk factor for cognitive decline due to Alzheimer’s disease (AD) in aging veterans. Synapses, the nodes at which neurons connect to one another to form networks, are frequently injured in trauma. Synapses are also a common target of neurodegenerative conditions such as AD, where their loss is the strongest predictor of cognitive decline. Immune system activation in the brain (neuroinflammation) is powerfully induced by TBI, and is responsible for synapse loss in AD. This study seeks to structurally and functionally define synaptic injury in a militarily relevant model of diffuse TBI, determine the role of neuroinflammatory factors in traumatic synapse loss, and connect these findings with long-term neurodegeneration. These advances will identify new targets for improving outcomes for service members after TBI, and for preventing TBI from progressing to AD.

PI_NAMEs: KUMMER, TERRANCE T (contact)

PROJECT_TERMS: active duty;Acute;Admixture;Adolescent and Young Adult;Adult;advanced disease;Affect;Age;aged;Aging;Alzheimer associated neurodegeneration;Alzheimer's Disease;Alzheimer's disease risk;Amyloid;Amyloidosis;analysis pipeline;Animal Model;APP-PS1;Atrophic;Automobile Driving;axon injury;Behavior monitoring;Behavioral;Brain;Brain region;Cause of Death;Chronic;Chronic disability;Cognitive;Complement;complement pathway;Complex;cost;Data;Dementia;Diffuse;disability;Elements;Emotional;Environmental Risk Factor;Epigenetic Process;Evaluation;Excitatory Synapse;falls;Fright;Functional disorder;functional improvement;functional outcomes;Genetic;gray matter;Head;Health;Human;Human Resources;Image;Image Analysis;immune activation;Immune system;Impaired cognition;improved outcome;Indolent;Inflammatory;injured;Injury;Innate Immune System;innovation;Interruption;Life;Link;loss of function;Measures;Mediating;Mediator;middle age;Military Personnel;Modeling;Molecular;Monitor;mouse model;Nanostructures;Nerve Degeneration;neural circuit;neural network;neurobehavioral;Neurofibrillary Tangles;neuroinflammation;Neurological disability;neuron loss;Neurons;Neuropil;Neuropsychology;novel;Outcome;Pathologic;Pathology;Pathway interactions;Pattern;pharmacologic;Play;presynaptic;prevent;Process;Public Health;resilience;response;Risk Factors;Role;Senile Plaques;service member;social;stem;superresolution imaging;Synapses;tau aggregation;tau Proteins;Tauopathies;TBI treatment;therapeutic target;Time;tool;Trauma;Traumatic Brain Injury;Veterans;War;white matter;young adult

PROJECT_TITLE: Imaging Synaptic Injury in TBI using SEQUIN


PHR: Project Narrative This application is for renewal of the SRCS program of Dr. Anjan Kowluru who is recognized globally for his pioneering work in the area of islet β-cell metabolism in health and diabetes. Dr. Kowluru will continue to investigate precise signaling mechanisms that underlie metabolic stress-induced mitochondrial dysfunction and nuclear collapse culminating in β-cell failure in diabetes. This innovative and highly translational program utilizes state-of-the-art experimental approaches involving islets derived from human donors (control and diabetic) and animal models for diet-induced obesity and diabetes. The established track record of Dr. Kowluru and his long-standing collaborations in the field will provide a unique opportunity to address these important aspects of islet function in health and diabetes. Data accrued from these investigations are expected to provide actionable insights that will impact the prevention and treatment of diabetes in humans, including our Veterans.

PI_NAMEs: KOWLURU, ANJANEYULU  (contact)

PROJECT_TERMS: Address;Affect;American;Animal Model;Apoptotic;Area;Attenuated;Award;Beta Cell;Biochemical Pharmacology;Biological;career;Caring;Catalytic Domain;Cell model;Cell Physiology;Cells;Cellular Metabolic Process;Ceramides;Chronic;Collaborations;Complex;Data;Defect;Development;Diabetes Mellitus;diabetic;Diabetic mouse;Diabetic Retinopathy;diet-induced obesity;Disease;Endocrine;Endocrinology;Endothelial Cells;Environment;exhaustion;Exposure to;Failure;Functional disorder;functional loss;Future;Glucose;GTP-Binding Proteins;Guanine Nucleotide Dissociation Inhibitors;Health;Healthcare;Healthcare Systems;high risk;Human;Hyperglycemia;impaired glucose tolerance;Impairment;In Vitro;in vivo;in vivo Model;Incidence;indexing;Individual;inhibitor;innovation;insight;Insulin;insulin granule;Insulin Resistance;insulin secretion;International;Investigation;Investments;islet;Journals;Knowledge;Laboratories;lipidomics;Lipids;Mediating;Medical;meetings;Mentors;Metabolic;Metabolic Diseases;Metabolic dysfunction;Metabolic stress;Metabolism;Methodology;Methylation;Microscopic;military veteran;Mission;Mitochondria;mitochondrial dysfunction;Molecular;Monomeric GTP-Binding Proteins;next generation;Non-Insulin-Dependent Diabetes Mellitus;novel;novel therapeutic intervention;Nuclear;Obesity;Oxidative Stress;Pathogenesis;Pathway interactions;Peer Review;Peptides;Peripheral;permissiveness;Phosphoric Monoester Hydrolases;Physiological;Physiology;Post-Traumatic Stress Disorders;Predisposition;prenylation;prevent;Prevention;Productivity;programs;Protein phosphatase;Proteins;Proteomics;Publications;Publishing;Regulation;Reporting;Research;Research Personnel;response;restoration;Retina;Rodent;Role;Saturated Fatty Acids;Scientist;Seminal;Signal Pathway;Signal Transduction;Signaling Protein;small molecule;small molecule inhibitor;Sphingolipids;Structure of beta Cell of islet;Therapeutic;therapeutic target;Time;Tissues;trafficking;Training;Transcriptional Activation;Veterans;Veterans Health Administration;Work;Writing


ORG_CITY: LOMA LINDA

ORG_NAME: VA LOMA LINDA HEALTHCARE SYSTEM

ORG_STATE: CA

PHR: Project Narrative One of the major complications of traumatic brain injury (TBI), a signature combat injury in Veterans, is heterotopic ossification (HO) that adversely affects the quality of life. Our ongoing translational research focused on identifying mechanisms and signaling molecules for TBI effects on HO will lead to the future development of effective rehabilitation strategies to minimize the adverse effects of TBI on HO and improve the general well- being of TBI patients in the VA and in the general population. Our other VA and NIH funded studies utilize state- of-the-art approaches to identify the cellular and molecular events that contribute to the pathogenesis of osteoarthritis and osteoporosis, two common musculoskeletal diseases affecting the Veterans. The goal of our research program is to identify and solve research questions that will ultimately lead to identification of novel therapeutic approaches to prevent and treat these bone diseases in the Veteran and general population.

PI_NAMEs: MOHAN, SUBBURAMAN  (contact)

PROJECT_TERMS: Adult;Adverse effects;Affect;Age;age related;aged;Aging;Area;Ascorbic Acid;Ascorbic Acid Deficiency;Award;bone;bone cell;Bone Diseases;bone fracture repair;bone loss;Bone Marrow;bone mass;bone metabolism;Book Chapters;career;Cartilage;chronic pain;Clinical;Collaborations;combat injury;combat zone;comorbidity;Complement Factor H;Degenerative polyarthritis;design;Development;diabetic patient;Diagnosis;Drug Targeting;effective therapy;Elderly;Elements;Epigenetic Process;Event;Family;Financial Hardship;Fracture;Functional disorder;functional status;Funding;Future;General Population;Generations;Genes;Genetic Transcription;Goals;Health;health care delivery;Healthcare;Heterotopic Ossification;high risk;hospitalization rates;Hydroxylation;Hypoxia;Impairment;improved;indexing;Injury;insight;International;Knock-out;Laboratories;Lead;Life Style;Long term physical disability;Mediating;Medical;meetings;member;men;Mentors;Metabolic Bone Diseases;Metabolism;mild traumatic brain injury;military service;military veteran;Minerals;Mission;Molecular;mortality;Musculoskeletal;Musculoskeletal Diseases;neurotransmission;new therapeutic target;Non-Insulin-Dependent Diabetes Mellitus;notch protein;novel;novel therapeutic intervention;Nuclear;Obesity;Osteoclasts;Osteogenesis;Osteoporosis;Oxygen;Pathogenesis;Pathway interactions;patient population;Personal Satisfaction;Phosphotransferases;Population;prevent;Prevention strategy;Process;Procollagen-Proline Dioxygenase;Productivity;programs;Promoter Regions;Proteins;Public Health;Publications;Publishing;Quality of life;Regulation;rehabilitation strategy;Research;Research Peer Review;Research Personnel;Research Priority;response;Role;Scientist;Seminal;sensor;service member;Signal Pathway;Signal Transduction;Signaling Molecule;skeletal abnormality;Skeletal system;soft tissue;stem cells;Survivors;TBI Patients;Tertiary Protein Structure;Therapeutic;Thyroid Hormone Receptor beta 2;Tight Junctions;Time;Tissues;TNFSF11 gene;Translational Research;Trauma;Traumatic Brain Injury;treatment strategy;United States National Institutes of Health;Veterans;Wasting Syndrome;Woman;Work


ORG_CITY: CHICAGO

ORG_NAME: JESSE BROWN VA MEDICAL CENTER

PHR: Growth hormone (GH) and insulin-like growth factor I (IGF1) are critical for body growth from birth through puberty. In adults, GH and IGF1 also control metabolism and may help the body repair after injury. GH and IGF1 are reduced in obese and diabetic patients. The reduction of GH and IGF1 may contribute to more weight gain, increase the severity of diabetes and cause fat to build up in the liver, ultimately leading to liver injury (referred to as non-alcoholic steatohepatitis [NASH]). NASH increases the risk of developing liver cancer and is now recognized as the leading cause for liver transplantation. In addition, the reduction in IGF1 may contribute to poor wound healing observed in diabetic patients. Work conducted in my laboratory explores the possibility that enhancing GH or IGF1 action may protect against the development of NASH and speed wound healing. These basic studies may reveal unique targets that can be used to develop therapies to treat the consequences of obesity and diabetes, which are common in Veterans.

PI_NAMEs: KINEMAN, RHONDA D (contact)

PROJECT_TERMS: Acromegaly;adeno-associated viral vector;Adipose tissue;Adult;Age;Animals;Anterior Pituitary Gland;Area;Aryl Hydrocarbon Receptor;Award;Biochemical;Birth;Book Chapters;Cardiovascular Diseases;career;Cells;Chicago;Citric Acid Cycle;Clinical;Clinical Research;Closure by clamp;Collaborations;combat veteran;comorbidity;Complement Factor H;Cues;Data;delivery vehicle;Development;Diabetes Mellitus;diabetic;diabetic patient;diabetic wound healing;Diet;Dietary Fatty Acid;Disease;Disease Progression;Doctor of Philosophy;Dopamine Receptor;Drug Targeting;editorial;Endocrinology;Enterobacteria phage P1 Cre recombinase;Enzymes;Estrogen Receptors;Etiology;Exclusion;experimental study;extracellular;Faculty;Fasting;Fatty acid glycerol esters;Fatty Acids;Feedback;Fibrosis;Foundations;Funding;Future;Gene Expression;Gene Proteins;General Population;Genes;Glucose Clamp;glucose production;Glycolysis;Grant Review;Growth;growth hormone deficiency;Growth Hormone Receptor;Growth Hormone Secreting Pituitary Neoplasm;Growth Hormone Signaling Pathway;Guanine + Cytosine Composition;Health;Hepatic;Hepatocyte;hormonal signals;hormone resistance;Hormone secretion;Human;Hyperglycemia;Hyperinsulinism;Hypothalamic structure;Illinois;Impairment;improved;Inflammation;Injury;Insulin;Insulin Receptor;Insulin Resistance;insulin sensitivity;Insulin-Like Growth Factor I;Insulin-Like-Growth Factor I Receptor;Internet;Investigation;JAK2 gene;Journals;Knock-out;Laboratories;Lactation;Leadership;leptin receptor;lipid biosynthesis;Lipolysis;Liver;liver injury;liver transplantation;Malignant neoplasm of liver;Manuscripts;Mediating;Medical center;Medicine;meetings;member;Metabolic;Metabolic Diseases;metabolic phenotype;Metabolism;military veteran;Modeling;Molecular;mouse model;Mus;Mutation;Neuroendocrinology;Non obese;non-alcoholic fatty liver disease;Non-Insulin-Dependent Diabetes Mellitus;nonalcoholic steatohepatitis;obese patients;Obesity;Pathway interactions;Patients;Pattern;Peer Review;Physiology;Pituitary Gland;Pituitary Hormones;Plasma;post-doctoral training;prevent;Production;promoter;protective effect;protein expression;Proteins;Puberty;Publishing;reconstitution;repaired;Reporting;repository;Reproduction;Research;Research Personnel;Risk;Role;Science;Scientist;Seminal;Services;Severities;Signal Pathway;Signal Transduction;Societies;Solid;Somatostatin Receptor;Somatotrope Cell;Somatotrophin increased;Somatotropin;Speed;stable isotope;therapy development;Thyroxine-Binding Globulin;tissue injury;tissue repair;Tissues;tool;Toxic Environmental Substances;Tracer;transgene delivery;treatment response;treatment strategy;tumor;tumor progression;United States National Institutes of Health;Universities;Veterans;vibration;Weight Gain;Work;wound healing


ORG_CITY: SAN DIEGO

ORG_NAME: VA SAN DIEGO HEALTHCARE SYSTEM

PHR: Serious mental illnesses such as schizophrenia account for a large portion of inpatient care at the VA and current medications do not adequately treat symptoms. Identifying potential risk factors, biomarkers, and early symptoms will be important to help screen military personnel at risk for serious mental illness and provide opportunities for early intervention. For example, in schizophrenia social withdrawal occurs early in the course of illness, prior to symptoms of psychosis, and predicts conversion to psychosis. The mechanism through which social withdrawal/isolation contributes to the progression of symptoms and neuropathology in schizophrenia is not known. Preclinical studies in model organisms will help inform progress in this area. The proposed studies will determine the impact of social isolation in rodents on cortico-limbic circuitry and cognitive deficits with the goals of identifying biomarkers predictive of susceptibility and developing more efficacious early interventions for neuropsychiatric disorders, particularly schizophrenia.

PI_NAMEs: POWELL, SUSAN B (contact)

PROJECT_TERMS: Address;Adolescence;Agonist;Animal Model;Antipsychotic Agents;Anxiety;Area;Attenuated;Behavior;Behavioral;Biological Markers;biomarker identification;Caring;Clinical Research;clinically relevant;Cognition;Cognitive;Cognitive deficits;cognitive function;cognitive reappraisal;Cognitive remediation;Corpus striatum structure;cost estimate;Data;Deterioration;Development;Early Intervention;Early treatment;effective therapy;emerging adult;Equilibrium;excitatory neuron;Fiber;flexibility;frontal lobe;Functional disorder;Future;gamma-Aminobutyric Acid;glutamatergic signaling;Glutamates;Goals;Hippocampus;hospital bed;Human;Immunohistochemistry;Impaired cognition;Impairment;improved;in vivo;Individual;inhibitory neuron;inpatient service;Intervention;Long-Term Care;Measures;medication compliance;Mental Depression;Mental disorders;metabotropic glutamate receptor 2;Metabotropic Glutamate Receptors;Military Personnel;model organism;Modeling;neural circuit;neurochemistry;Neurons;neuropathology;neuropsychiatric disorder;neuropsychiatry;neuroregulation;optogenetics;Pathologic Processes;Pathology;Pharmaceutical Preparations;pharmacologic;Photometry;potential biomarker;Precipitating Factors;preclinical study;predictive marker;Predisposition;prevent;Prognosis;progression marker;Psychoses;Psychotic Disorders;Quality of life;Rattus;Reporting;Research;Resources;Reversal Learning;Risk;Risk Factors;Rodent;Schizophrenia;severe mental illness;Severities;side effect;social;Social isolation;symptom treatment;Symptoms;Testing;Therapeutic Intervention;therapeutic target;therapy development;Time;treatment response;Veterans;Weaning;Withdrawal;Work

PROJECT_TITLE: Impact of social isolation on cognitive function and neural circuitry abnormalities


ORG_CITY: SEATTLE

ORG_NAME: VA PUGET SOUND HEALTHCARE SYSTEM

ORG_STATE: WA

PHR: Many Veterans have experienced mild traumatic brain injuries (also called “concussions”) when they were too close to an explosion during their military service in Afghanistan and Iraq. We now know that years after returning home, many of these Veterans continue to have distressing and often disabling symptoms such as headaches, memory problems, disturbed sleep, irritability, and poor impulse control. These blast brain injuries make it more likely that a Veteran will develop the type of brain degeneration widely recognized in football players who have suffered multiple concussions. The proposed animal and human studies will address the large gaps in our knowledge about the brain damage that results from blast. Such new knowledge will help provide direction for new treatments for Veterans suffering from the consequences of blast mild traumatic brain injuries.

PI_NAMEs: MEABON, JAMES STEPHAN (contact)

PROJECT_TERMS: Ablation;Afghanistan;Aging;Alzheimer's Disease;Anatomy;Animals;Arousal;Attention;Auditory;Autopsy;Back;Behavior;Behavioral;Bilateral;Brain;Brain Concussion;Brain Injuries;brain tissue;Canine Adenoviruses;case control;Cellular Stress;Cerebellum;Cerebrospinal Fluid;Characteristics;Chronic Phase;Cognition;Cognitive;cognitive function;Color;common symptom;comparison control;Data;Dentate nucleus;Diffusion Magnetic Resonance Imaging;Diphtheria Toxin;disability;disabling symptom;Distress;Enzymes;Exhibits;experience;Explosion;Fiber;flexibility;fluorodeoxyglucose positron emission tomography;glucose uptake;Goals;Green Fluorescent Proteins;Headache;Hippocampus;Home;Human;Impairment;Injections;Injury;Iraq;Knock-out;Knowledge;Label;Length;Lesion;locus ceruleus structure;Lysophosphatidylcholines;Manufactured football;Mediating;Memory;mild traumatic brain injury;military service;Modeling;mouse model;Mus;Myelin;Nature;Nerve Degeneration;Neurons;noradrenergic;Norepinephrine;Performance;Phenotype;Post-Concussion Syndrome;pressure;Publishing;Reporter;Rodent Model;Scanning;service member;Short-Term Memory;Signal Transduction;single-cell RNA sequencing;Sleep disturbances;Structure;Symptoms;Testing;transcriptomics;Transgenic Organisms;translational study;Tyrosine 3-Monooxygenase;Up-Regulation;Veterans;Viral;War;white matter;white matter injury

PROJECT_TITLE: Translational Study of Blast mTBI Effects on Locus Ceruleus-Cerebellar Network Structure and Function


ORG_CITY: MEMPHIS

ORG_NAME: MEMPHIS VA MEDICAL CENTER

PHR: Post-traumatic osteoarthritis (PTOA) is highly prevalent in military personnel and veterans. There is no effective pharmacological treatment for PTOA. This proposal aims to promote regeneration of cartilage of the joint to halt the progression of PTOA by harnessing joint-resident cartilage precursors and stem cells. Results of this project will be highly translatable into clinical development for a novel therapy for PTOA in humans.

PI_NAMEs: HASTY, KAREN A. (contact)

PROJECT_TERMS: Acute;Address;Adipose tissue;Affect;Animals;Anti-Inflammatory Agents;Antibodies;Arthralgia;articular cartilage;behavior change;Biological Assay;Biomechanics;bone marrow mesenchymal stem cell;Cartilage;cartilage degradation;Cartilage injury;cartilage regeneration;cartilage repair;CD14 gene;cellular targeting;Charge;Chondrocytes;Chondrogenesis;chondrogenesis factor;Clinical;clinical development;Collagen Type II;Cumulative Trauma Disorders;Degenerative polyarthritis;Disease;economic impact;experimental study;Fibrocartilages;functional improvement;Genes;Goals;Green Fluorescent Proteins;Histopathology;Human;Hyaline Cartilage;Hybrids;imaging system;Immunohistochemistry;improved;In Situ;In Vitro;in vivo;Inflammation;Inflammatory;Intervention;Intra-Articular Injections;joint function;joint injury;Joints;Knee joint;Liposomes;loss of function;Macrophage;Measures;Medial meniscus structure;Mesenchymal Stem Cells;Methods;Military Personnel;military service;military veteran;Modeling;monocyte;Natural Immunity;Natural regeneration;novel therapeutics;Pain;pain relief;particle;Pathogenesis;Pathway interactions;Penetration;Pharmacological Treatment;Play;Polymers;precursor cell;Procedures;Property;protective effect;Rattus;repaired;response;Role;service member;Site;socioeconomics;Standardization;Stem Cell Mobilization;stem cell self renewal;stem cells;subchondral bone;Surface;synergism;Synovial Fluid;Synovial Membrane;Synovitis;System;targeted delivery;Technology;Testing;Therapeutic Effect;therapeutic evaluation;Therapeutic procedure;Time;TLR4 gene;transcription factor;Traumatic Arthropathy;Treatment Protocols;Veterans

PROJECT_TITLE: Stimulation of Native Joint-resident Precursors for Cartilage Repair in Osteoarthritis


ORG_CITY: WEST HAVEN

ORG_NAME: VA CONNECTICUT HEALTHCARE SYSTEM

ORG_STATE: CT

PHR: Ischemia reperfusion injury (IRI) predisposes to chronic antibody-mediated rejection (CABMR) and worsened outcomes for veteran transplant recipients. Complement (C’) are immune proteins that injure endothelial cells (EC) during IRI, and Hedgehog (Hh) is a mitogenic pathway promoting wound healing. We found that graft EC injured by C’ during IRI elaborated Hh ligands that selectively expanded T peripheral helper (TPH) cells, a newly discovered T cell subset involved in B cell help, to promote CABMR. We explore mechanisms by which EC-derived Hh ligands assemble TPH cell intrinsic NLRP3 inflammasomes to mediate expansion of these cells. We then test salient molecule(s) in two humanized mouse models and assess their clinical relevance in patient specimens. This work implicates Hh signaling as a new druggable pathway to block IRI-induced complications and to improve graft survival in veteran transplant patients.

PI_NAMEs: JANE-WIT, DANIEL  (contact)

PROJECT_TERMS: Address;Affect;Allografting;antibody-mediated rejection;Antigen-Presenting Cells;Area;Autologous;B-Lymphocytes;Basic Science;Biochemical;Biological Assay;Blood flow;Blood Vessels;Caring;CD4 Positive T Lymphocytes;cell injury;Cell Physiology;Cell Proliferation;Cells;Chronic;Clinical;clinically relevant;Complement;Complement Membrane Attack Complex;Complication;cost;Data;delayed graft function;Diagnostic;Donor person;donor-specific antibody;effective therapy;Endothelial Cells;Erinaceidae;FDA approved;genetic approach;Graft Survival;Health;Health Services Accessibility;Healthcare Systems;Helper-Inducer T-Lymphocyte;Host Defense;Human;humanized mouse;Hypoxia;IL18 gene;Immune;Immunoglobulin M;implantation;improved;In Vitro;in vitro Model;in vivo;Inflammasome;injured;Isoantibodies;isoimmunity;Kidney Transplantation;Lead;Lesion;Ligands;Link;Mediating;Medical;Modeling;Molecular;mouse model;Natural Immunity;novel;Operative Surgical Procedures;Organ Transplantation;Outcome;Pathologic;Pathologic Processes;Pathology;Pathway interactions;Patient-Focused Outcomes;Patients;Peripheral;pharmacologic;phosphoproteomics;Phosphorylation;Population;Postoperative Period;Process;Production;Property;prospective;Proteins;Reperfusion Injury;Respondent;response;Risk;Rodent;Role;Sampling;Signal Transduction;Site;smoothened signaling pathway;Solid;Specimen;System;T-Lymphocyte;T-Lymphocyte Subsets;Testing;Tissues;Transplant Recipients;Transplantation;Transplantation Immunology;Vascular Diseases;vascular inflammation;Veterans;Work;wound healing

PROJECT_TITLE: Hedgehog-Induced Activation of Alloimmune T Cells During Ischemia Reperfusion Injury


ORG_CITY: MADISON

ORG_NAME: WM S. MIDDLETON MEMORIAL VETERANS HOSP

ORG_STATE: WI

PHR: Veteran patients are at increased risk for the development of ischemic heart disease due to traditional atherosclerotic risk factors and service-related exposures such as combat and herbicides. In addition, acute myocardial infarction and heart failure carry high morbidity and mortality among Veterans, with a recent study reporting a 30-day mortality rate of 13.7% and 11.4%, respectively. While current therapies for ischemic heart disease target cytoplasmic signaling cascades, the neuro-hormonal system and mechanical reperfusion and electrical therapy, many cell survival pathways converge on the mitochondria. Unfortunately, no specific therapies currently target this organelle. The goal of this project is to study the mechanisms underlying cardioprotection from a sulfonylurea 2A splice variants (SUR2A) that target mitochondria. I hypothesize that mitochondrial targeted SUR2A regulates the putative mitochondrial ATP sensitive potassium channel and cardiac glucose metabolism and is crucial to cardioprotection during ischemic cardiac syndromes.

PI_NAMEs: RAMRATNAM, MOHUN  (contact)

PROJECT_TERMS: Acute myocardial infarction;atherosclerosis risk;ATP sensitive potassium channel complex;Cardiac;Cardiac Myocytes;Cardiology;Cardiomyopathies;cardioprotection;career;career development;Cell Survival;Clinic;Clinical;clinical practice;Collaborations;combat;Core Facility;cost;Coupled;Cytoplasm;Data;Death Rate;Dedications;Development;educational atmosphere;Electron Transport;Environment;Equipment;experience;fatty acid metabolism;fatty acid oxidation;Fatty Acids;Fellowship;Fostering;Foundations;Funding;Generations;Genetic;Glucose;glucose metabolism;Glycolysis;Goals;Heart;Heart failure;heart function;heart metabolism;Herbicides;Hospitals;human induced pluripotent stem cells;improved;induced pluripotent stem cell derived cardiomyocytes;inherited cardiomyopathy;Injury;Inner mitochondrial membrane;Institution;interest;Internal Medicine;Intervention;Ischemia;ischemic injury;Ischemic Preconditioning;Kidney;knock-down;Knock-out;Knockout Mice;Knowledge;Laboratories;loss of function;Mass Spectrum Analysis;Mechanics;medical schools;Medicine;Mentors;Mentorship;Metabolic;Metabolism;Mitochondria;mitochondrial metabolism;mitochondrial permeability transition pore;Modeling;Molecular;Molecular Structure;Morbidity - disease rate;mortality;mouse model;Mus;Myocardial;Myocardial Infarction;Myocardial Ischemia;Myocardial Reperfusion Injury;Neonatal;new therapeutic target;novel;novel therapeutics;Organelles;Outcome;overexpression;Pathway interactions;Patients;pharmacologic;Physicians;Potassium Channel;preference;preservation;prevent;Process;professor;programs;Protein Isoforms;protein protein interaction;Proteomics;Public Health;recruit;Reperfusion Injury;Reperfusion Therapy;Reporting;Research;Research Project Grants;Residencies;Resistance;Resources;Respiration;response;Rest;Risk;Risk Factors;RNA Splicing;Role;Scientist;Services;Signal Transduction;skills;Societies;Sulfonylurea Compounds;sulfonylurea receptor;Syndrome;System;targeted treatment;Testing;Time;Training;Transgenic Organisms;translational therapeutics;Universities;Variant;Veterans;Veterans Health Administration;Wisconsin;Work

PROJECT_TITLE: The mechanism of cardio-protection from a sulfonylurea receptor isoform 2 splice variant (SUR2A-55) and its role in regulating ROMK activity, the putative mitochondrial ATP sensitive potassium channel