ORG_CITY: CLEVELAND

ORG_NAME: LOUIS STOKES CLEVELAND VA MEDICAL CENTER

PHR: Acute Myeloid Leukemia (AML) is a rapidly progressing disease that develops from immature hematopoietic cells. Unfortunately, the prognosis of most patients is extremely poor with the average patients over the age of 56 surviving less than 2 years. Despite the poor outcomes, there has been no change in standard therapy in over 40 years. AML is a particularly important disease in the VA population as the outcomes of VA patients are inferior to those in the general population. The purpose of this proposal is to investigate a new strategy that may be useful in developing an improved therapy for AML. Therefore, the proposed work is of major significance to VA patients and their families.

PI_NAMEs: WALD, DAVID  (contact)

PROJECT_TERMS: Acute leukemia;Acute Myelocytic Leukemia;acute myeloid leukemia cell;Adult;Affect;Age;Alkaloids;analog;Animals;Antineoplastic Agents;Biological Assay;cell growth;Cells;Cessation of life;Chemistry;clinical application;Complement;Cross Reactions;Development;Disease;Drug Targeting;enzyme activity;Enzyme Inhibition;Enzymes;Exhibits;Family;General Population;Genetic;Genetic study;glutathione peroxidase;Glutathione Reductase;Glycolysis;Grant;Growth;hazard;Hematopoietic;Human;human model;Immunodeficient Mouse;Impairment;improved;In Vitro;in vivo;Individual;Inferior;inhibitor;Lead;lead optimization;leukemia;Measurement;Mediating;Metabolic;Metabolism;metabolomics;Military Personnel;mitochondrial metabolism;Modeling;Molecular Target;Morbidity - disease rate;mortality;mouse model;Mus;nanomolar;neoplastic cell;Normal Cell;novel;novel therapeutics;Outcome;Oxidation-Reduction;Oxidoreductase;Patients;Pharmaceutical Chemistry;Pharmaceutical Preparations;pharmacologic;Pharmacology Study;Plants;Play;Population;Prognosis;Property;Proteins;Reporting;Role;Series;Solid Neoplasm;Solubility;Specificity;Sulfhydryl Compounds;System;Testing;Therapeutic;therapeutic development;thioredoxin reductase;Toxic effect;tumor metabolism;TXN gene;Work

PROJECT_TITLE: Targeting metabolism in AML


ADMINISTERING_IC: AI

ARRA_FUNDED: N

ED_INST_TYPE: SCHOOLS OF MEDICINE

FUNDING_MECHANISM: NON-SBIR/STTR RPGS

IC_NAME: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES

NIH_SPENDING_CATS: Antimicrobial Resistance;Biotechnology;Clinical Research;Immunization;Infectious Diseases;Microbiome;Prevention;Urologic Diseases;Vaccine Related

ORG_CITY: SAINT LOUIS

ORG_COUNTRY: UNITED STATES

ORG_DEPT: INTERNAL MEDICINE/MEDICINE

ORG_FIPS: US

ORG_NAME: WASHINGTON UNIVERSITY

ORG_STATE: MO

PHR: NARRATIVE Urinary tract infections (UTIs) affect 15 million women in the US every year and are predominantly caused by uropathogenic E. coli (UPEC). The major adhesin of UPEC, FimH, is needed for colonization of the urinary tract and gut and vaccines targeting FimH have been shown to protect from UTIs, although the mechanism(s) of protection is unknown. This proposal will define how antibodies directed against FimH prevent infection and gut colonization with UPEC.

PI_NAMEs: KAU, ANDREW LEON (contact)

PROGRAM_OFFICER_NAME: XU, ZUOYU

PROJECT_TERMS: Activities of Daily Living;Address;Adherence;Affect;Affinity;Animal Model;Animals;Antibiotic Resistance;Antibiotic Therapy;Antibiotics;Antibodies;Antibody Formation;Antibody Response;Antibody Specificity;Area;ascending urinary tract infection;B-Lymphocytes;Bacterial Adhesins;bacterial community;Binding;Bladder;Blocking Antibodies;cancer therapy;Cell Separation;Cells;Coal;combat;Communicable Diseases;Communities;Cystitis;Data;design;Development;Diagnostic;Distal;effectiveness testing;Epithelium;Epitopes;Equilibrium;Escherichia coli;Extended-spectrum β-lactamase;fluoroquinolone resistance;Gastrointestinal tract structure;Generations;Genome;Gnotobiotic;gut colonization;gut microbiota;Host Defense Mechanism;Human;human monoclonal antibodies;humanized monoclonal antibodies;Immune;Immune System Diseases;Immunization;Immunoglobulin G;Immunoglobulin-Secreting Cells;Impairment;in vivo;Infection prevention;Invaded;Light;Mannose;Mannosides;Mediating;microbial community;Modeling;Molecular Conformation;Monkeys;Monoclonal Antibodies;mouse model;mucosal vaccination;Mucous Membrane;Multi-Drug Resistance;Mus;Mutation;Operon;Oral Administration;Passive Immunization;Pathogenesis;Pathogenicity;Patients;Persons;Phase Ia/Ib Clinical Trial;Pilum;Prevalence;prevent;Prevention;Production;Public Health;receptor;Recombinants;Recurrence;Research;Resistance;resistant strain;Resolution;response;Role;Serinus;Signal Transduction;Specificity;Surface;Tertiary Protein Structure;Testing;Therapeutic;Therapeutic Uses;Thinking;Time;United States;Urethra;Urinary tract;Urinary tract infection;Urine;Uropathogen;Uropathogenic E. coli;Vaccinated;Vaccination;Vaccines;Virus Diseases;Woman

PROJECT_TITLE: Harnessing Antibody Responses to Prevent and Treat Urinary Tract Infections

STUDY_SECTION: VMD

STUDY_SECTION_NAME: Vaccines Against Microbial Diseases Study Section[VMD]


ADMINISTERING_IC: VA

IC_NAME: Veterans Affairs

ORG_CITY: CINCINNATI

ORG_NAME: CINCINNATI VA MEDICAL CENTER RESEARCH

ORG_STATE: OH

PHR: Posttraumatic Stress Disorder (PTSD) is a disabling psychiatric condition that is highly prevalent in combat veterans. Only a fraction of trauma-exposed individuals develop PTSD, suggesting that pre-existing neurobiological factors contribute to susceptibility/ risk. Significant gaps remain in our understanding of PTSD risk especially at the molecular-circuit level. This Merit review application focuses on how neurovascular signaling activates novel fear circuits that may contribute to PTSD susceptobility. Using a preclinical mouse paradigm of CO2-sensitivity-PTSD behaviors modeled on observations of pre-deployment CO2-sensitivity predicting PTSD in combat veterans, our studies will provide a mechanistic basis for PTSD risk. Impact on Patient Care: The goal of this research is to identify neurobiological risk factors that will lead to predictive biomarkers and therapeutics for management of PTSD in at-risk veterans.

PI_NAMEs: SAH, RENU  (contact)

PROJECT_TERMS: Acidosis;Air;Angiotensin II;Angiotensin-Converting Enzyme Inhibitors;antagonist;Area;Attenuated;attenuation;Behavior;Blood - brain barrier anatomy;Brain;Brain region;Captopril;Carbon Dioxide;Cells;combat veteran;conditioned fear;Data;Development;Disabling;Electrophysiology (science);emotion regulation;Endothelial Cells;Endothelium;Extinction;Female;Fright;Functional disorder;genetic approach;Genetic Polymorphism;Goals;IL1R1 gene;Impairment;Individual;Individual Differences;Inhalation;Interleukin-1 Receptors;Intervention;Link;Losartan;male;Measures;military veteran;Modeling;Molecular;mouse model;Mus;Neurobiology;Neuroimmune;Neurons;neurovascular;novel;Outcome;patch clamp;Patient Care;Peptidyl-Dipeptidase A;Pharmacology;Post-Traumatic Stress Disorders;pre-clinical;predictive marker;Predisposition;Prosencephalon;Reaction;Receptor, Angiotensin, Type 1;Regulation;Renin-Angiotensin System;Reporter;Reporting;Research;resilience;response;Risk;Risk Factors;risk prediction;Role;Saline;Sensory;Shapes;Signal Transduction;Slice;Structure of terminal stria nuclei of preoptic region;Subfornical Organ;Symptoms;Testing;Therapeutic;therapeutic target;Transgenic Organisms;Trauma;trauma exposure;Veterans;Work

PROJECT_TITLE: Neurovascular signaling and associated forebrain circuits in PTSD


ORG_CITY: SALT LAKE CITY

ORG_NAME: VA SALT LAKE CITY HEALTHCARE SYSTEM

ORG_STATE: UT

PHR: (Pro)renin receptor (PRR) is a new member of the renin-angiotensin system (RAS) and has emerged as a key regulator of renal handling of Na+ and water balance, blood pressure (BP), and the intrarenal RAS. Protease- mediated cleavage of PRR generates soluble PRR (sPRR), the extracellular domain of this protein. Circulating sPRR is widely regarded as a biomarker for a number of human diseases such as cardiovascular disease, chronic kidney disease, etc. Recently, we first reports a novel biological function of sPRR in regulation of fluid balance. While furin and ADAM19 were originally thought to mediate sPRR production, new evidence demonstrated site-1 protease (S1P) as the predominant cleavage enzyme. Therefore, the goal of this proposal is to define the regulation and function of S1P- derived sPRR in renal handling of Na+ balance and BP. Compelling preliminary data demonstrated that S1P is indispensable to Aldo-induced ENaC activation and is also implicated in the development of salt- sensitive hypertension in Dahl S (SS) rats via generation of sPRR. It is further intriguing that sPRR directly interacts and activates angiotensin type 1 receptor (AT1R) to induce α-ENaC expression. Therefore, we hypothesize that S1P-derived sPRR induced ENaC activation via interaction with AT1R, thus serving a common downstream pathway responsible for salt-sensitive hypertension. To test this hypothesis, we will define the function of S1P/sPRR in different salt-sensitive hypertensive models with use of pharmacological inhibitors or renal tubule-wide deletion of S1P. Reversibility of the effect of S1P inhibition is tested by supplement of exogenous sPRR. Lastly, we propose to test the direct interaction between sPRR and AT1R and further explore its implication in regulation of ENaC. Overall, this proposal is expected to offer novel insight into the function of a newly described S1P/sPRR pathway in the kidney.

PI_NAMEs: YANG, TIANXIN  (contact)

PROJECT_TERMS: Anti-Hypertensive Agents;Attenuated;Binding;Biological Markers;Biological Process;Blood Pressure;Cardiovascular Diseases;Chronic Kidney Failure;Data;Development;Enzymes;epithelial Na+ channel;Equilibrium;Extracellular Domain;Fluid Balance;Generations;Goals;human disease;Hypertension;hypertension treatment;hypertensive;Inbred Dahl Rats;inhibitor;Injury to Kidney;insight;Kidney;Mediating;member;Modeling;neutralizing antibody;novel;Pathogenesis;Pathway interactions;Peptide Hydrolases;pharmacologic;Production;Rattus;receptor;Receptor Signaling;Receptor, Angiotensin, Type 1;Regulation;Renal tubule structure;Renin;Renin-Angiotensin System;Renin-Angiotensin-Aldosterone System;Reporting;Role;salt sensitive;salt sensitive hypertension;site-1 protease;Tertiary Protein Structure;Testing;Water

PROJECT_TITLE: Defining renal S1P/sPRR/AT1R pathway  in salt-sensitive hypertension


FUNDING_MECHANISM: OTHERS

ORG_CITY: TAMPA

ORG_NAME: JAMES A. HALEY VA MEDICAL CENTER

ORG_STATE: FL

PHR: My research focuses on identification of novel, effective treatments for Veterans’ conditions that currently have no effective treatments, including Traumatic Brain Injury, Gulf War Illness and Posttraumatic Stress Disorder. These are currently typically addressed by attempted repurposing of existing drugs, rather than development of new drugs specifically targeting their underlying pathobiology. My team and I have developed mouse models of all of these conditions, which we then use to understand the molecular mechanisms causing the negative outcomes, working closely with clinicians, and clinical samples from patients, in order to be sure that our models are relevant to the human condition. We have been successful in advancing novel treatments for Alzheimer’s Disease and Gulf War Illness into clinical trials, and this experience provides a roadmap and informs my ongoing and future endeavors.

PI_NAMEs: CRAWFORD, FIONA C. (contact)

PROJECT_TERMS: Acute;Address;Adopted;Agonist;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease patient;Amyloid;Amyloid beta-Protein;Animal Model;Anti-Hypertensive Agents;Anti-Inflammatory Agents;Area;Attention;Autopsy;Award;Awareness;Behavioral;Biochemical;Biological Availability;Biological Markers;Blood;Blood specimen;Brain;brain tissue;career;Cell model;Cells;Cerebrovascular system;Chronic;Clinical;clinical application;Clinical Trials;clinically relevant;Collaborations;Data;Development;Diagnostic;dietary supplements;Dihydropyridines;Disease;disease-causing mutation;Dose;drug discovery;Drug Kinetics;effective therapy;Ensure;Evaluation;experience;Exposure to;Formulation;Functional disorder;Funding;Future;Genes;genetic manipulation;Genomics;Genotype;Goals;Healthcare;Heterogeneity;Human;I-kappa B Proteins;Immune;Inflammatory;inhibitor;Injury;Intervention;Investigation;Laboratories;Lead;Life;life span;mild traumatic brain injury;Military Personnel;military veteran;Modeling;Molecular;Molecular Target;mouse model;Mus;Nervous System Disorder;Nervous System Trauma;Neurodegenerative Disorders;Neuroimmunomodulation;neuroinflammation;neuropsychiatric disorder;Neurosciences Research;new therapeutic target;novel;novel therapeutic intervention;novel therapeutics;Nutraceutical;old mice;oleoylethanolamide;Outcome;Pathogenicity;Pathologic;patient population;Patients;Persian Gulf Syndrome;Pharmaceutical Chemistry;Pharmaceutical Preparations;Pharmacodynamics;Phase;Phase II Clinical Trials;Phase III Clinical Trials;Post-Traumatic Stress Disorders;pre-clinical;Productivity;programs;Property;Publications;Rationalization;Recording of previous events;Research;research clinical testing;Research Personnel;research study;response;response to injury;Role;Route;Sampling;Scientist;severe injury;Signal Pathway;Signal Transduction;Stress;SYK gene;tau Proteins;Therapeutic;Therapeutic Intervention;therapeutic target;Time;Tissue Sample;Toxic effect;Toxicant exposure;Translations;Traumatic Brain Injury;treatment response;verification and validation;Veterans;Work

PROJECT_TITLE: BLRD RESEARCH CAREER SCIENTIST AWARD APPLICATION


ORG_CITY: BALTIMORE

ORG_NAME: BALTIMORE VA MEDICAL CENTER

ORG_STATE: MD

PHR: Strokes and related diseases consume 5% of Veteran Health Administration (VHA) patient care resources and about 15,000 Veterans annually receive acute inpatient care for stroke. Reducing the death, disability and economic burden of stroke is a major VHA priority. Genetics is a potentially powerful tool for better understanding disease etiology as it can highlight biological mechanisms underlying disease and point the way to improved prevention and treatment strategies, which, ultimately, will be personalized to each individual’s genome. The proposed international study will more than 19,000 cases of ischemic stroke among adults ages 18-59 and a similar number of controls. Exome-sequencing of all samples will be performed in collaboration with an industry partner, Regeneron. The project will be the largest study by far to examine the hypothesis that rare protein-coding genetic variants are associated with early-onset ischemic stroke.

PI_NAMEs: COLE, JOHN W. (contact)

PROJECT_TERMS: Acute;Address;Adult;African;African ancestry;Age;Age of Onset;Agreement;Asian ancestry;Big Data;biobank;Biological;Biological Markers;Caucasians;Cause of Death;Cessation of life;Code;Collaborations;Complement;Complex;Consumption;Data;Development;disability burden;Disease;Drug Targeting;early onset;Economic Burden;Etiology;European;exome sequencing;Exons;experience;Genes;Genetic;genetic association;Genetic Code;Genetic Risk;Genetic study;genetic variant;Genome;genome wide association study;genomic locus;Genomic medicine;Genotype;Goals;Healthcare;Heritability;Hispanic;Hispanic ancestry;improved;Individual;industry partner;inpatient service;insight;International;Investments;Ischemic Stroke;Leadership;Letters;Methods;non-genetic;novel;novel therapeutic intervention;older adult;Onset of illness;Pathway interactions;Patient Care;Penetrance;personalized medicine;Phenotype;Population;Positioning Attribute;Predisposition;Prevention;Prevention strategy;programs;Proteins;rare variant;Research;Resources;Role;Sampling;Stress;Stroke;Stroke prevention;Susceptibility Gene;Testing;tool;trait;Trans-Omics for Precision Medicine;treatment strategy;Variant;Veterans;Veterans Health Administration

PROJECT_TITLE: Whole Exome Sequencing Study of Early-Onset Ischemic Stroke


ORG_CITY: NORTHPORT

ORG_NAME: NORTHPORT VA MEDICAL CENTER

ORG_STATE: NY

PHR: NARRATIVE Fungal infections are a major source of morbidity and mortality in veterans with compromised immune systems as a result of AIDS, substance abuse, or whose going under treatment for malignancy, autoimmune disease, or organ transplantation. Antifungal therapies are often inadequate and fungal resistant organisms to current antifungals are in the rise. Thus, studies that enhance knowledge of microbial pathogenesis and pulmonary host defense are essential for the development of new therapeutic strategies to treat these patient populations. Dr. Del Poeta’s studies identify and examine a new class of antifungal agents, a new fungal vaccine and new fungal and host pathways involved in the fungal pathogenic process. His studies also dissect interactions of microbial factors with host defenses to identify mechanisms of fungal evasion. These studies are an essential step in design new therapies against these infections.

PI_NAMEs: DEL POETA, MAURIZIO  (contact)

PROJECT_TERMS: Acquired Immunodeficiency Syndrome;Adrenal Cortex Hormones;Animal Model;anti-fungal agents;Antifungal Therapy;Aspergillus fumigatus;Autoimmune Diseases;Award;Biological Assay;Brain;Candida albicans;career;CD4 Positive T Lymphocytes;Cell Count;Cells;Ceramides;Cessation of life;chemotherapy;Clinic;Clinical;Collaborations;Communicable Diseases;Communities;Containment;cross reactivity;Cryptococcal Meningitis;Cryptococcosis;Cryptococcus;Cryptococcus neoformans;Death Rate;Dependence;design;Development;Disease;Drug Design;Drug Formulations;Drug resistance;Educational process of instructing;Effectiveness;Ensure;Environment;Enzymes;experience;Exposure to;Faculty;Fungal Vaccines;fungus;General Population;Glucosylceramides;Goals;Granuloma;Growth;Hand;high throughput screening;HIV;Host Defense;Immune Evasion;Immune system;Immunity;Immunocompromised Host;immunoregulation;Industry;Infection;inhibitor;Injections;Inositol;Integration Host Factors;interest;Intervention;Investigation;Knowledge;Laboratories;Lipids;Lung;Malignant Neoplasms;Mediating;Medical;Medical center;microbial;microorganism interaction;military service;Molecular;Morbidity - disease rate;mortality;multiple sclerosis treatment;Mycoses;novel;novel therapeutic intervention;novel therapeutics;opportunistic pathogen;Organ Transplantation;Organism;Pathogenesis;Pathogenicity;Pathway interactions;patient population;Patients;Pharmaceutical Chemistry;Pharmaceutical Preparations;Phenotype;Physicians;Population;Postdoctoral Fellow;Predisposition;Preventive;Process;Research;research and development;Research Personnel;Resistance;Scientist;Services;small molecule;Source;South Carolina;Specificity;Sphingolipids;sphingomyelin synthase;Sphingomyelins;sphingosine 1-phosphate;SPHK1 enzyme;Spinal Cord;Structure;Students;Substance abuse problem;Symptoms;Technology;Testing;The science of Mycology;Therapeutic;Therapeutic immunosuppression;therapeutically effective;Toxic effect;Toxicology;Training;Universities;Veterans;Virulence;Work

PROJECT_TITLE: BLRD Research Career Scientist Award Application


ORG_CITY: Aurora

ORG_NAME: VA EASTERN COLORADO HEALTH CARE SYSTEM

ORG_STATE: CO

PHR: Nontyphoidal Salmonella are a common cause of diarrhea in healthy individuals and a fatal systemic complication in patients with underlying immunodeficiencies. Salmonella is the most common cause of bacteremia in HIV--‐infected people. Salmonellosis is a frequent infection in veterans, their families and military personnel deployed abroad. Salmonella and other bacteria associated with diarrhea are increasingly becoming resistant to multiple antibiotics. The Center for Disease Control’s National Resistance Monitoring System reported that roughly 20% of Salmonella blood isolates in the US are resistant to first--‐line drugs. We will continue to build on our understanding of Salmonella pathogenesis for the development of novel therapeutics against multidrug resistant Salmonella and other bacteria.

PI_NAMEs: VAZQUEZ-TORRES, ANDRES  (contact)

PROJECT_TERMS: absorption;Alzheimer's Disease;Amino Acids;Aminoglycoside resistance;Aminoglycosides;Anabolism;Antibiotic Resistance;antibiotic tolerance;Antibiotics;antimicrobial;Award;Bacteremia;Bacteria;Bacterial Antibiotic Resistance;beta-Lactams;Binding;Blood;Burkholderia pseudomallei;career;Cell division;Cell Wall;Centers for Disease Control and Prevention (U.S.);Cessation of life;Clinical;Collaborations;Colorado;Complex;Complication;Cytochromes;Development;Diarrhea;DNA-Directed RNA Polymerase;Electron Transport;enteric pathogen;Enzymes;Escherichia coli;Evolution;Excretory function;Faculty;Family;Fostering;fundamental research;Funding;Genetic Transcription;global health;Goals;graduate student;Grant;Growth;Guanosine Tetraphosphate;Health;Healthcare Systems;HIV;immunodeficiency;improved;Individual;Infection;Inflammation Mediators;International;Intestines;Investigation;Journals;Knowledge;Legal patent;Macrophage;Mediating;Mediator;Medical center;Mentors;Metabolic;Metabolic Pathway;Metabolism;microbial;Military Personnel;misfolded protein;Mission;Molecular;Monitor;Multi-Drug Resistance;NADPH Oxidase;Nature;next generation;Nitric Oxide;non-typhoidal Salmonella;NOS2A gene;novel;novel therapeutics;Nucleotides;Oxidation-Reduction;Paper;Parkinson Disease;pathogen;Pathogenesis;pathogenic bacteria;Patients;Persons;Phagocytes;Pharmaceutical Preparations;Play;Poison;Poisoning;Postdoctoral Fellow;preclinical study;Productivity;programs;Protein Biosynthesis;Proteins;Publishing;Purines;rational design;Regulation;Reporting;Research;Research Personnel;Research Project Grants;Resistance;response;Rod;Role;Salmonella;Salmonella infections;Sampling;Schedule;Science;Scientist;Secondary to;Seminal;Site;System;Training;training opportunity;transcription factor;Transcriptional Elongation Factors;Translating;Translations;Tubulin;Type III Secretion System Pathway;United States Department of Veterans Affairs;Universities;Veterans;Virulence;Wisconsin;Work;World Health Organization


ORG_CITY: SAN ANTONIO

ORG_NAME: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM

ORG_STATE: TX

PHR: Project Narrative:  An often overlooked symptom associated with Alzheimer's disease (AD) is psychosis (hallucinations and delusions), which are reported in over 50% of AD patients. Unfortunately, the antipsychotic medications used to treat psychosis are contraindicated in the elderly where they increase the risk of death. Here we examine the mechanisms contributing to comorbid psychosis in AD and evaluate whether pharmacological manipulation of hippocampal GABAergic signaling may be a potentially novel therapeutic approach for the symptoms of AD and comorbid psychosis.

PI_NAMEs: LODGE, DANIEL  (contact)

PROJECT_TERMS: Affect;Agonist;Alzheimer's Disease;Alzheimer's disease model;Alzheimer's disease pathology;Alzheimer's disease patient;American;Antipsychotic Agents;associated symptom;Autopsy;Behavior;Behavioral;Belief;Black Box;care costs;Cell Transplantation;cholinergic;comorbidity;Delusions;Dementia;Development;Disease;disorder risk;Dopamine;dopamine system;dopaminergic neuron;effective therapy;Elderly;Electrophysiology (science);Exons;extracellular;Functional disorder;Generations;Glutamates;Hallucinations;Hippocampus;Human;in vivo;Injury;Interneuron function;Interneurons;Knock-in;Locomotion;Memory;Midbrain structure;Military Personnel;military veteran;Modeling;mortality risk;Mutation;Neurons;neurotransmission;new therapeutic target;novel;novel therapeutic intervention;Parvalbumins;Pathologic;Pathology;Patients;Pharmaceutical Preparations;pharmacologic;Play;Population;positive allosteric modulator;Post-Traumatic Stress Disorders;prepulse inhibition;presenilin-1;preservation;Prevalence;Psychoses;psychotic symptoms;Rattus;receptor;Regulation;Reporting;response;Rodent Model;Role;Schizophrenia;Services;Signal Transduction;Site;Somatostatin;spatial memory;Stem cell transplant;Stimulant;Structure;Swedish mutation;Symptoms;Therapeutic;Toxic effect;Transplantation;Traumatic Brain Injury;United States Food and Drug Administration;Ventral Tegmental Area;Veterans

PROJECT_TITLE: Mechanisms contributing to co-morbid psychosis in Alzheimer's disease


ORG_CITY: NASHVILLE

ORG_NAME: VETERANS HEALTH ADMINISTRATION

ORG_STATE: TN

PHR: Project Narrative The goals of our research programs are to elucidate molecular mechanisms of tumor angiogenesis, cancer metabolism, and anti-tumor immunity, and to translate our discoveries towards improved cancer therapy. We use state-of-the-art technologies and novel animal models to dissect signaling and metabolic pathways underlying the pathogenesis of lung cancer, which affects a large population of our VA patients and greatly impact on the quality of life of our veterans. Success of our research will not only improve our understanding of development and progression of lung cancer, but also lead to timely cancer therapies to benefit VA patients.

PI_NAMEs: CHEN, JIN  (contact)

PROJECT_TERMS: Affect;angiogenesis;Angiogenic Factor;Animal Model;Animals;Area;Award;Binding;Blood Vessels;Bypass;cancer cell;Cancer Patient;cancer subtypes;cancer therapy;career;Categories;Cells;checkpoint receptors;Chemical Exposure;Chemicals;Circulation;Classification;Clinic;Clinical Trials;Data;design;Development;Disease;Dose;driver mutation;Drug resistance;EGFR gene;Endothelium;EphA2 Receptor;Ephrin-A1;Epidermal Growth Factor Receptor;Exposure to;FDA approved;Feedback;FRAP1 gene;Funding;Glutaminase;Glutamine;Goals;Healthcare;high standard;Hyperactivity;Immune;immune checkpoint blockade;immune function;Immunotherapy;improved;Incidence;inhibitor;Investigation;kinase inhibitor;Knock-out;Knockout Mice;KRAS2 gene;Laboratories;lipid biosynthesis;Lipids;Lymphocyte;Lymphocytic Infiltrate;Malignant neoplasm of lung;Malignant Neoplasms;Manuscripts;Mediating;Metabolic;Metabolic Pathway;Metabolism;Military Personnel;military veteran;Mission;Molecular;molecular targeted therapies;mTOR Signaling Pathway;mutant;Mutation;Neoplasm Metastasis;Neoplasms in Vascular Tissue;neoplastic cell;neovascularization;new therapeutic target;Non-Small-Cell Lung Carcinoma;novel;Nutrient;Oncogenic;overexpression;Pathogenesis;Patient Care;Patients;Pharmaceutical Preparations;Phosphotransferases;Point Mutation;Population;pre-clinical;programs;Publishing;Quality of life;recruit;Refractory;Regulation;Research;Resistance;Role;Scientist;screening;SDZ RAD;Signal Pathway;Signal Transduction;small molecule inhibitor;Smoking;success;T-Cell Activation;T-Lymphocyte;targeted treatment;Technology;Testing;Therapeutic;therapeutic target;Transcription Coactivator;Transcriptional Activation;Translating;translational potential;tumor;Tumor Angiogenesis;tumor growth;Tumor Immunity;tumor metabolism;tumor progression;tumor-immune system interactions;Tumor-Infiltrating Lymphocytes;United States National Institutes of Health;Up-Regulation;Validation;Veterans;War;Work

PROJECT_TITLE: BLRD Merit Review Research Career Scientist (RCS) Award (IK6)


ORG_CITY: CHICAGO

ORG_NAME: JESSE BROWN VA MEDICAL CENTER

ORG_STATE: IL

PHR: Project Narrative: A number of reports suggest, high incidence of pancreatic cancer (PDAC) in ageing veterans with diabetes and veterans from Vietnam War. The PDAC is projected to be a second leading cause of cancer-related death in the United States by 2030 and currently being managed with chemotherapeutic agents such as Gemcitabine and nab-paclitaxel, which only modestly improve survival. Based on our results, we outline a series of experiments to investigate therapeutic efficacies of a kinase (MAP4K4) inhibitor along with immunotherapy for a better therapeutic option to manage PDAC in future.

PI_NAMEs: RANA, AJAY NMN (contact)

PROJECT_TERMS: Address;Affect;Aging;Animal Cancer Model;Animal Model;Animals;Antibodies;Antineoplastic Agents;Apoptosis;Apoptotic;Cancer Etiology;cancer therapy;Cell Death;Cell Line;Cells;Cessation of life;Chemoresistance;chemotherapeutic agent;clinically significant;Combined Modality Therapy;conventional therapy;Cytotoxic T-Lymphocytes;Data;Desmoplastic;Development;Devices;Diabetes Mellitus;druggable target;Ductal Epithelial Cell;effector T cell;efficacy evaluation;efficacy testing;expectation;experimental study;FDA approved;Future;gemcitabine;Granzyme;Human;Immune;Immunity;Immunotherapy;improved;Incidence;Infiltration;Inflammation;Inflammatory;inhibitor;interest;KPC model;KRAS oncogenesis;KRAS2 gene;Laboratories;Link;Malignant neoplasm of pancreas;Malignant Neoplasms;MAP4K4 gene;Mus;mutant;Mutation;Neoplasm Metastasis;neoplastic;novel;Oncogenic;Outcome;overexpression;Paclitaxel;Pancreas;Pancreatic Ductal Adenocarcinoma;pancreatic ductal adenocarcinoma model;Pathogenesis;Pathway interactions;Patient-Focused Outcomes;Patients;Peripheral;Pharmaceutical Preparations;Phenotype;Phosphorylation;Phosphotransferases;Physiological;Play;pre-clinical;Proliferating;Protein Family;Rationalization;Reporting;Research;Resistance;response;Role;Series;Severities;Signal Pathway;Survival Rate;T cell infiltration;T-Lymphocyte;Therapeutic;Therapeutic Intervention;Time;Tissues;TNF gene;Treatment Efficacy;treatment strategy;tumor;Tumor Burden;tumor microenvironment;United States;upstream kinase;Veterans;Vietnam;War

PROJECT_TITLE: Rational Combination of MAP4K4 Inhibition and Immunotherapy in Pancreatic Cancer


ORG_CITY: Decatur

ORG_STATE: GA

PHR: The research program of Aliza Wingo, MD, MSc, addresses the VA priority research areas including PTSD, Alzheimer’s dementia, women veteran’s health, and genomic medicine. Particularly, Dr. Wingo studies the genetic and molecular mechanisms that underlie the conditions that disproportionally affect Veterans - PTSD, depression, Alzheimer’s dementia, and detrimental effects of maternal PTSD on offspring outcomes. Another important aspect of Dr. Wingo’s research effort is to elucidate the genetic and molecular basis of resilience, conceptualized as adaptive coping in the context of stress, adversity, or trauma. In this novel and cutting-edge CDTA application, Dr. Wingo proposes to identify proteins in the human brain that i) predispose one to PTSD or depression, and ii) contribute to resilience after adverse or traumatic life experiences. From these studies, Dr. Wingo hopes to contribute to a better understanding of the neurobiology of PTSD, depression, and Alzheimer’s dementia in order to find more effective interventions and enhance resilience among Veterans.

PI_NAMEs: WINGO, ALIZA PHAM (contact)

PROJECT_TERMS: Address;Affect;Alzheimer's Disease;Anxiety;Area;Autopsy;Award;Awareness;Behavioral;Biological Models;Biological Psychiatry;Blood;Board Certification;Brain;brain tissue;career;Caring;Chromosome 1;Cognitive;Communication;comorbid depression;Complex;coping;Data;Data Set;Dementia;dementia risk;Development;DICER1 gene;Doctor of Medicine;effective intervention;Elderly;epidemiology study;Etiology;Event;experience;Female;Formulation;Funding;Future;Genes;Genetic;Genetic study;genetic variant;genome wide association study;Genomic medicine;Genotype;geriatric depression;Goals;Health;Healthcare;high risk;Human;Impaired cognition;Individual;innovation;intergenerational;Intervention;Journals;K-Series Research Career Programs;Life;Life Experience;Mass Spectrum Analysis;Meaning and purpose;Medical center;Mental Depression;Messenger RNA;Meta-Analysis;MicroRNAs;Modeling;Molecular;mRNA Expression;Multiomic Data;multiple omics;National Institute of Mental Health;Nature;Neurobiology;novel;novel therapeutic intervention;novel therapeutics;offspring;Outcome;Paper;Participant;Pathway interactions;Patient Care;positive emotional state;Post-Traumatic Stress Disorders;Prefrontal Cortex;Pregnant Women;Principal Investigator;programs;promote resilience;protective effect;protein expression;Proteins;Proteome;Proteomics;Psyche structure;Psychiatrist;Psychiatry;psychologic;Publications;Publishing;Regulation;Research;Research Personnel;Research Priority;resilience;resilience biomarker;Role;Seminal;Shapes;statistics;Stress;Symptoms;Systems Biology;Techniques;transcriptome;transcriptomics;Transition Career Development Award (K22);Translating;Trauma;United States National Institutes of Health;Veterans;Weight;Woman;Work

PROJECT_TITLE: BLR&D Research Career Development Transition Award Application


ORG_CITY: INDIANAPOLIS

ORG_NAME: RLR VA MEDICAL CENTER

ORG_STATE: IN

PHR: Roughly 25% men over the age of 50 will suffer an osteoporotic fracture during their senior years, and the 1- year mortality rate following a hip fracture is nearly 2× as high for men as for women. One-fifth of those who were ambulatory before their hip fracture require long-term care afterward. Beyond their age, other lifestyle factors make veterans particularly susceptible to osteoporosis, including smoking, alcohol consumption, and an inactivity. Moreover, many Vietnam veterans were exposed to environmental factors during the war, such as the dioxin TCDD (found in Agent Orange), which put them at much greater risk for osteoporosis. Recently, the VA amended its adjudication regulation to establish a presumption of service connection for osteoporosis for former Prisoners of War (POWs) who were detained or interned for at least 30 days, and more recently, for those diagnosed with posttraumatic stress dis-order (PTSD), and whose osteoporosis is at least 10% disabling. There is a clear need to identify new treatment options for veterans that suffer from low bone mass disease.

PI_NAMEs: ROBLING, ALEXANDER G (contact)

PROJECT_TERMS: Address;adjudication;Adult;Adverse event;Affect;Age;Age Years;agent orange;Alcohol consumption;Amendment;American;Award;Basic Science;Bed rest;Binding;Biomechanics;Black Box;bone;Bone Diseases;bone health;bone loss;bone mass;bone metabolism;bone preservation;Bone Tissue;C57BL/6 Mouse;carboxylesterase;cardiovascular risk factor;Cardiovascular system;Cell Lineage;cell type;Cells;Complex;cortical bone;Cre driver;Data;Death Rate;Defect;Development;Diagnosis;Dioxins;Disabling;Disease;Effector Cell;Engineering;Environmental Risk Factor;Enzyme-Linked Immunosorbent Assay;Erinaceidae;Event;experimental study;Exposure to;Fatty acid glycerol esters;Fatty Acids;FDA approved;Fracture;fracture risk;Future;Gene Expression;Genetic Transcription;Glucocorticoids;Glycoproteins;Goals;Health;High Prevalence;High Risk Woman;Hip Fractures;Homeostasis;Human;improved;Inflammatory Bowel Diseases;inhibitor;Internships;Knock-out;Knockout Mice;Label;lifestyle factors;Ligands;Limb Bud;Long-Term Care;LoxP-flanked allele;Measures;Mechanics;Mediating;medication safety;men;Mesenchymal;Methods;military veteran;Modeling;Monkeys;Mus;Muscle;Mutant Strains Mice;Mutation;Myocardial Infarction;neutralizing antibody;novel;Organ Transplantation;Osteoblasts;osteoclastogenesis;Osteoclasts;Osteocytes;Osteogenesis;Osteopenia;Osteoporosis;osteoporosis with pathological fracture;Paralysed;Pathway interactions;Patients;Persons;pharmacologic;phase III trial;Phenotype;Population;Porosity;post-market;Post-Traumatic Stress Disorders;Postmenopause;Pre-Clinical Model;Predisposition;Prisoner;programs;Property;Proteins;radiological imaging;Rattus;receptor;Regulation;Research;response;Rheumatoid Arthritis;Risk;Risk Factors;Serum;Serum Markers;Services;side effect;Signal Pathway;Signal Transduction;Site;skeletal;skeletal disorder;Skeleton;Smoking;Steroids;Stroke;success;Tail;Tetrachlorodibenzodioxin;Therapeutic;therapy development;tumor;Veterans;Vietnam;War;wasting;Wasting Syndrome;Woman;Work

PROJECT_TITLE: Harnessing the anabolic potential of Wnt signaling to improve bone health


ORG_CITY: SAN FRANCISCO

ORG_NAME: VETERANS AFFAIRS MED CTR SAN FRANCISCO

ORG_STATE: CA

PHR: Traumatic brain injury (TBI) is a widespread and devastating problem that affects all ages, but with particular high incidence for soldiers in the military. Neuroinflammation is a significant component of secondary brain injury that can worsen brain damage. Current results from strategies targeting innate immunity to treat acute brain injury are encouraging. We use an experimental mouse model of TBI to apply elegant approaches to study neuroinflammation. For this proposal, we seek to better understand changes in the immune response to TBI over time, including during chronic TBI. In collaboration with pharmaceutical companies, we test the efficacies of therapeutic approaches that have not been tested in TBI before to alter inflammation and improve functional behavior outcomes in preclinical studies. In particular, we will determine the cellular mechanisms driving a potent innate immune pathway propagated by type I interferons in TBI, and test targeting these cells/pathway to treat TBI in preclinical studies. Our goal is to improve functional recovery for veterans.

PI_NAMEs: HSIEH, CHRISTINE LINDA (contact)

PROJECT_TERMS: Acute;Acute Brain Injuries;Affect;Age;Alzheimer's disease model;Animal Model;Anti-Inflammatory Agents;Antisense Oligonucleotide Therapy;Antisense Oligonucleotides;Apoptotic;Applications Grants;Automobile Driving;Behavior;Behavioral;behavioral outcome;Biological Markers;biomarker identification;Brain;Brain Injuries;cell injury;cell type;Cells;chemokine;Chronic;Clinic;Collaborations;Communication;conditional knockout;Cues;cytokine;Dangerousness;Data;design;Development;disability;Disease;Disease associated microglia;effective therapy;efficacy testing;Environment;Evaluation;Experimental Models;functional improvement;functional outcomes;Gene Expression;Gene Expression Profile;Genes;Genetic;Genomics;Goals;Government;Growth Factor;Health Care Costs;Heterogeneity;Histology;Histopathology;Homeostasis;Hour;Human;IFNAR1 gene;Immune;Immune response;improved;improved outcome;Incidence;Infection;Infiltration;Inflammation;Inflammatory;Injury;innate immune pathways;Interferon Receptor;Interferon Type I;Interferons;knock-down;Knowledge;Lesion;Leukocytes;Link;Macrophage;Mediating;Methods;Microglia;Military Personnel;Molecular;mouse model;mRNA Expression;Multiple Sclerosis;Mus;Natural Immunity;Nerve Degeneration;neuroinflammation;Neurons;neuroprotection;Neurosciences Research;neurotoxic;novel;novel therapeutic intervention;Outcome;pathogen;Pathology;Pathway interactions;Patients;Persons;Phagocytosis;pharmacologic;Pharmacologic Substance;Pharmacological Treatment;Plasma;preclinical study;preservation;Production;Proliferating;Publishing;receptor;Recovery of Function;recruit;repaired;response;RNA;Role;Sentinel;Sex Differences;Signal Transduction;single-cell RNA sequencing;Site;Soldier;Specificity;STING1 gene;Surveys;synaptic pruning;Synaptophysin;TBI treatment;Testing;Therapeutic;therapeutic target;Time;tissue repair;transcription factor;Traumatic Brain Injury;Treatment Efficacy;Veterans;Vision;wound healing

PROJECT_TITLE: Analysis of a Type I Interferon Responsive Microglia Subset in Traumatic Brain Injury


PHR: Accumulation of toxic proteins (i.e. Aβ42 & tau) and dysfunctional mitochondria are associated with synaptic and neuronal loss in multiple neurodegenerative disorders, including Alzheimer’s disease (AD). This application utilizes cellular and animal models combined with molecular gene expression tools to understand the mechanistic basis of toxic tau protein and dysfunctional mitochondria accumulation in AD pathogenesis. The proposed studies are expected to shed novel insights to how a defined and separable function of SSH1 protein mediates these processes.

PI_NAMEs: KANG, DAVID E (contact)

PROJECT_TERMS: Alzheimer's Disease;Alzheimer's disease brain;Alzheimer's disease model;Amyloid beta-42;Amyloid beta-Protein;Animal Model;Apoptosis;APP-PS1;Autophagocytosis;Binding;Binding Sites;Biochemical;Biological;Biological Assay;Brain;C-terminal;Catalytic Domain;Cell model;Cells;Co-Immunoprecipitations;cofilin;Complex;Defect;Dominant-Negative Mutation;F-Actin;Gene Expression;Homologous Gene;Hydrogen Peroxide;hyperphosphorylated tau;Impairment;in vivo;indexing;insight;Knowledge;Learning;Ligation;Link;Lysosomes;Mediating;Memory;Microtubules;Mitochondria;mitochondrial dysfunction;Molecular;mouse model;Mus;mutant;Mutation;Neurodegenerative Disorders;neuron loss;Neurons;novel;Outcome;Oxidative Stress;Oxidative Stress Induction;Pathogenesis;Pathway interactions;Phosphorylation;Play;Process;Protein Dephosphorylation;Protein phosphatase;Proteins;Publishing;receptor;Role;Synapses;System;tau aggregation;tau Proteins;Tauopathies;Testing;tool;Transfection;Variant;Viral

PROJECT_TITLE: Divergent roles of Slingshot-1 in tauopathy


PHR: Spinal cord injury is a debilitating condition that afflicts hundreds of thousands of people worldwide. In the United States alone, there are approximately 12,000 new cases that occur each year and about 270,000 people now live with spinal cord injury. The economic cost of spinal cord injury is substantial, estimated at tens of thousands of dollars per patient every year. Treatments that promote the recovery of some lower-extremity motor and sensory activity after a complete paraplegic spinal cord injury could have significant value. Currently, effective treatments are limited. There are relatively few efforts to develop small-molecule therapeutic agents to treat spinal cord injury patients. In this project, we propose to develop small molecules that could lead to therapeutic agents that could be used either alone, or in combination with existing therapies. We expect that small molecules that inhibit a protein associated with the RhoA GTPase will promote axonal regrowth and lead to repair and recovery in spinal cord injury patients.

PI_NAMEs: MEROUEH, SAMY ;WHITE, FLETCHER A (contact)

PROJECT_TERMS: Affinity Chromatography;aggrecan;Animal Model;Animals;antagonist;Axon;axon growth;axon regeneration;Binding;Biological Assay;Biology;Blood;blood-brain barrier crossing;Brain;Cell Culture Techniques;chemical standard;Clinical Trials;clinically relevant;Contusions;Data;design;Development;Docking;Dorsal;Dose;Drug Industry;Drug Kinetics;druggable target;economic cost;effective therapy;Event;Exhibits;Fiber;Forelimb;Goals;Grant;Growth;Guanosine Triphosphate Phosphohydrolases;improved outcome;In Vitro;in vitro Assay;in vivo;in vivo Model;in vivo regeneration;Injury;innovation;insight;Investigational Drugs;Laboratories;Length;Lesion;Libraries;Lower Extremity;Mass Spectrum Analysis;Maximum Tolerated Dose;Mediating;Methods;Modeling;Monomeric GTP-Binding Proteins;Motor;Mus;Natural regeneration;Neurites;Neurons;neuroprotection;Paraplegia;Patients;Permeability;Persons;Pharmaceutical Chemistry;Positioning Attribute;Property;protein structure;Proteins;Recovery;Recovery of Function;repaired;screening;Sensory;Signal Transduction;Site;small molecule;Small Molecule Chemical Library;small molecule libraries;small molecule therapeutics;Spinal cord injury;Spinal cord injury patients;Structure;success;Testing;Therapeutic Agents;transcriptome sequencing;United States

PROJECT_TITLE: Small Molecules to Promote Regeneration and Recovery Following Spinal Cord Injury


ORG_CITY: SAN DIEGO

ORG_NAME: VA SAN DIEGO HEALTHCARE SYSTEM

PHR: New-onset asthma prevalence is up to 14% of previously healthy military personnel deployed to the middle east that now make up the majority of Veterans (over 7 million in 2016). Approximately 5-10% of all asthmatics have severe disease with very high morbidity and require the most health care costs. About half of severe asthma patients do not have allergic-type inflammation found in most with mild to moderate disease and currently have no specific targeted therapies available. We have developed a novel model of non-allergic severe asthma and have identified a potential therapeutic target, stimulator of interferon genes (STING), as critical to the severe asthma features of the model. We propose to uncover how STING and changes in a white blood cell population of innate lymphocytes might contribute to this novel severe asthma model. We will also characterize STING expression and function in human lung and blood samples including those with severe asthma. !

PI_NAMEs: DOHERTY, TAYLOR A (contact)

PROJECT_TERMS: Adoptive Cell Transfers;Adoptive Transfer;Adrenal Cortex Hormones;Agonist;airway hyperresponsiveness;airway inflammation;Allergens;Allergic;Alternaria;antagonist;Asthma;asthma model;asthmatic;asthmatic patient;Automobile Driving;Blood specimen;Bone Marrow;CD4 Positive T Lymphocytes;Cell secretion;cell type;Cells;Chimera organism;Cost of Illness;cytokine;Cytoplasmic Protein;Data;Detection;Disease;Donor person;eosinophil;Epithelial Cells;experimental study;Exposure to;Gene Expression;gene function;Goals;Health Care Costs;Helper-Inducer T-Lymphocyte;Human;In Vitro;in vivo;Inflammation;Inflammatory;Inflammatory Response;inhibitor;Interferon Receptor;Interferon Type II;Interferons;Interleukin-5;Interleukins;Knockout Mice;Leukocytes;Lung;Lymphocyte;Lymphoid Cell;Macrophage;Middle East;Military Personnel;Modeling;Morbidity - disease rate;Mucous body substance;Mus;Myelogenous;neutrophil;Neutrophilia;new therapeutic target;novel;Pathway interactions;Periodicity;peripheral blood;Peripheral Blood Mononuclear Cell;Phenotype;Play;Population;Prevalence;Production;Protocols documentation;Pulmonary Inflammation;receptor;Reporting;Research;Resistance;response;Role;Sampling;Second Messenger Systems;Signal Transduction;Source;STAT1 gene;Stimulator of Interferon Genes;T-Lymphocyte Subsets;targeted treatment;Therapeutic;therapeutic target;Transcript;transcriptome sequencing;translational impact;Veterans;Wild Type Mouse

PROJECT_TITLE: Roles of STING and innate lymphoid cell plasticity in severe asthma


ORG_CITY: RICHMOND

ORG_NAME: VA VETERANS ADMINISTRATION HOSPITAL

ORG_STATE: VA

PHR: Post-operative atrial fibrillation (POAF) affects 30%-50% of patients after coronary artery bypass grafting and/or valve surgeries. POAF leads to increased heart failure, hospital stays, healthcare expenditures and predicts the development of late AF. Increased activity of the cardiac ganglionated plexi (GP), a key component of the cardiac autonomic nervous system (CANS), is an important trigger and substrate for POAF and AF. We recently published in a canine model, that microinjection of nanoformulated CaCl2 into GP induces neuronal apoptosis, dampens the overactivity of the CANS that occurs after cardiac surgery and suppresses/prevents POAF without adverse effects or myocardial damage. Our goal is to validate the feasibility of our canine POAF model in swine species, to test the safety, efficacy and neuromodulation mechanism of POAF suppression by nanoformulated CaCl2.The potential benefits is a safe, effective and cost- effective method to prevent POAF and reduce susceptibility to AF long term.

PI_NAMEs: TAN, ALEX Y (contact)

PROJECT_TERMS: Acute;Adverse effects;Affect;Anatomy;Animal Model;Arrhythmia;Atrial Fibrillation;autonomic nerve;Autonomic nervous system;Calcium;Calcium Chloride;canine model;Canis familiaris;Cardiac;Cardiac Surgery procedures;Characteristics;Chronic;clinical translation;Complication;Coronary Artery Bypass;cost;cost effective;Data;Development;Electrophysiology (science);Family suidae;Glutamates;Glycolic-Lactic Acid Polyester;Goals;Health Expenditures;Heart;Heart Atrium;Heart failure;high risk population;Human;in vivo;in vivo Model;Incidence;Induced Neurons;Inflammation;Injury;injury and repair;Institution;Length of Stay;Mediating;Methods;Microinjections;military veteran;Miniature Swine;Modeling;myocardial damage;nano;nanoparticle;neural;neuron apoptosis;neuroregulation;novel;novel therapeutics;Operative Surgical Procedures;Patients;Pericardial body location;Pericarditis;porcine model;Postoperative Period;Predisposition;prevent;Prevention therapy;Publishing;Recurrence;Reporting;response;Risk;Safety;safety testing;Site;Surgical Models;Testing;Thoracotomy;Validation

PROJECT_TITLE: Validation of Swine Model for Testing a Novel Therapy for Postoperative Atrial Fibrillation using Nanoformulated Calcium Chloride to Suppress Cardiac Ganglionated Plexi


ORG_CITY: BOSTON

ORG_NAME: VA BOSTON HEALTH CARE SYSTEM

ORG_STATE: MA

PHR: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common cause of kidney and liver dysfunction that significantly reduces life expectancy and severely impacts quality of life in Veterans and their dependents. This costly disease ($2 billion/year) is caused by mutations in two proteins of unknown function called "polycystin 1" and "polycystin 2" that are associated with disturbances in intracellular signaling patterns of an important messenger molecule known as cyclic AMP (cAMP). Human clinical drug trials showed that the cAMP pathway is a promising target for controlling cyst growth in ADPKD, but existing drugs do not address the complete spectrum of the disease process. Our results indicate that cAMP could have positive and negative effects on cyst expansion depending on where in the cell this signal is generated. By investigating the finer details of how localized cAMP signals work in ADPKD cells, we expect to find more selective ways to inhibit cyst growth, and ultimately to preserve kidney function.

PI_NAMEs: HOFER, ALDEBARAN M (contact)

PROJECT_TITLE: Harnessing the potential of GPCRs localized to the primary cilium for the treatment of renal disease


PHR: A staggering 94.4% of our young veterans returning from the Global War on Terror with fragment projectiles and gunshot wounds will develop arthritis, presenting a serious need to regenerate permanent cartilage of their joints before the development of osteoarthritis and a lifetime of pain. This proposal builds upon our recently developed stem cell-based strategy of tissue regeneration by establishing the efficacy of readily available cell sources and physical therapy to repair articular cartilage defects, restore joint function, and alleviate pain. We believe our approach will ultimately circumvent a variety of limitations and move us towards an off-the-shelf solution to post-traumatic osteoarthritis.

PI_NAMEs: DRISSI, MOULAY HICHAM (contact)

PROJECT_TERMS: Activities of Daily Living;Address;Adipose tissue;Adolescent;Adult;adult stem cell;Affect;Afferent Neurons;allodynia;Animal Model;Animals;Arthralgia;arthritic pain;Arthritis;articular cartilage;Autologous;Biological;BMP2 gene;bone marrow mesenchymal stem cell;Cartilage;cartilage degradation;cartilage regeneration;cartilage repair;Cell Therapy;Cells;central pain;Chondrocytes;Chronic;chronic pain;Clinical Trials;Collaborations;common treatment;comparative efficacy;Cumulative Trauma Disorders;Data;Defect;Degenerative polyarthritis;density;Development;Disease;economic impact;Evaluation;Exercise;experimental study;Fibrocartilages;Fluoro-Gold;functional improvement;functional outcomes;Gait;Goals;Gunshot wound;Histologic;Human;Hyaline Cartilage;immunoregulation;implantation;improved;In Vitro;in vivo;Individual;induced pluripotent stem cell;Inflammation;Inflammatory;Infrastructure;inhibitor;Injury;innovation;joint function;joint injury;Joints;Knee;Label;Laboratories;Left;Link;loss of function;Mechanics;Mesenchymal Stem Cells;military service;Modality;Modeling;molecular imaging;Movement;muscle strength;Muscle Weakness;Natural Immunity;Natural regeneration;Nerve Endings;Neurologic;Nociception;novel;Operative Surgical Procedures;osteoarthritis pain;Pain;pain inhibition;Pain management;Pain Measurement;pain outcome;pain reduction;pain relief;Particulate;Pathway interactions;patient population;Patients;peptidomimetics;Periodicity;Pharmaceutical Preparations;Pharmacologic Substance;Physical Exercise;Physical Rehabilitation;Physical therapy;Physiology;Pluripotent Stem Cells;Pre-Clinical Model;preservation;prevent;programs;Rattus;reconstruction;Regenerative capacity;Regimen;Rehabilitation therapy;repair strategy;repaired;Reporting;Research;Research Personnel;response;restoration;Running;Sequential Treatment;service member;small molecule;Social Impacts;socioeconomics;Somatic Cell;Source;Spinal Ganglia;standard of care;Standardization;stem cell therapy;stem cells;Structure;subchondral bone;Swelling;Synovitis;Testing;Therapeutic;Tissue Engineering;tissue regeneration;tissue repair;Traumatic Arthropathy;Treatment outcome;treatment response;Vertebral column;Veterans;War;Weight-Bearing state

PROJECT_TITLE: CMA: Cartilage Repair Strategies to Alleviate Arthritic Pain (CaRe AP): Novel cell-based therapies to increase functional outcomes and alleviate pain in preclinical models of osteoarthritis


ORG_CITY: PITTSBURGH

ORG_STATE: PA

PHR: PROJECT NARRATIVE Stroke remains as the 5th leading cause of death and long-term adult disability in the USA. Moreover, hypertension and pre-hypertension are common in active US military personnel. Post-traumatic stress disorder is associated with different cardiovascular and cerebrovascular diseases in older veterans, including hypertension and ischemic stroke. This proposal is to understand cellular mechanisms underlying worsened ischemic stroke in hypertensive brains and to develop a novel therapeutic strategy for ischemic stroke with comorbid hypertension.

PI_NAMEs: SUN, DANDAN  (contact)

PROJECT_TERMS: Acute;Adult;Alanine;Alteplase;Angiotensin II;Angiotensin II Receptor;Angiotensin II Signaling Pathway;Blood Pressure;Brain;Brain Injuries;Brain Ischemia;Cardiovascular Diseases;Cause of Death;cell injury;Cerebrovascular Disorders;Cerebrum;Clinical Trials;Clover;comorbidity;Complex;cytotoxic;disability;Dissociation;Distal;Dose;Drug Kinetics;Edema;Epidemic;excitotoxicity;Exhibits;Family;Genes;Genetic Transcription;Hypertension;hypertensive;improved;improved outcome;inclusion criteria;Infarction;Ions;Ischemia;Ischemic Brain Injury;Ischemic Stroke;kinase inhibitor;Knowledge;Lysine;Mediating;Middle Cerebral Artery Occlusion;Military Personnel;Modeling;mortality risk;Mus;Nervous System Physiology;neurogenic hypertension;Neurologic Deficit;Neurons;Neuroprotective Agents;NF-kappa B;novel;novel strategies;novel therapeutic intervention;Nuclear Translocation;Outcome;Oxidative Stress;Pathogenesis;Patient-Focused Outcomes;Patients;Perfusion;Phosphorylation;Phosphotransferases;Pilot Projects;post stroke;Post-Traumatic Stress Disorders;prehypertension;prevent;Proline;protein complex;Protein Isoforms;Receptor, Angiotensin, Type 1;Recovery of Function;Resistance;Risk Factors;Serine;Signal Pathway;Signal Transduction;Stroke;stroke outcome;stroke patient;stroke therapy;symporter;Testing;Therapeutic;therapeutic target;Threonine;Up-Regulation;Veterans

PROJECT_TITLE: SPAK inhibitor ZT-1a for ischemic stroke therapy


PHR: Glycosaminoglycans (GAGs) are ubiquitous in nature and play important role in cancer. They have been found to regulate critical properties of cancer stem cells (CSCs), which are responsible for cancer recurrence and mortality. We have discovered that a non-sugar mimetic called G2.2 and its analogs selectively inhibit CSCs. We propose to generate more effective analogs of G2.2 with improved drug-like properties, and study their molecular mechanisms of action to decipher CSC biology, especially glycobiology, and develop novel anti-cancer therapies that address the issues of remission and/or cure.

PI_NAMEs: PATEL, BHAUMIK B (contact)

PROJECT_TERMS: Address;adult stem cell;analog;Animal Model;anti-cancer;Baltimore;Biological;Biological Assay;Biological Markers;Blood;cancer cell;Cancer Cluster;cancer immunotherapy;cancer recurrence;Cancer Relapse;cancer stem cell;cancer therapy;carcinogenesis;Carcinoma;Cell Surface Receptors;Cells;Chemoresistance;chemotherapy;Clinic;Clinical;Collaborations;Colon;colon cancer patients;Colon Carcinoma;Colonic Neoplasms;Colorectal;Colorectal Cancer;colorectal cancer treatment;Development;Disease remission;Distal;Drug Kinetics;efficacy evaluation;efficacy testing;Epidermal Growth Factor Receptor;Exhibits;FGF2 gene;FGFR1 gene;Fiber;Fibroblast Growth Factor Receptors;Fluorouracil;genetic variant;Genomics;Glycobiology;Glycosaminoglycans;Goals;Growth Factor;HT29 Cells;Human;Immunotherapy;improved;in silico;In Vitro;in vivo;in vivo Model;inhibitor;innovation;Insulin-Like-Growth Factor I Receptor;Intestines;Invaded;Knowledge;Malignant Neoplasms;Mediator;metabolomics;Methods;migration;mimetics;Modeling;Molecular;Molecular Mechanisms of Action;mortality;mutant;Nature;Neoplasm Metastasis;novel;Organ;Organoids;Outcome;oxaliplatin;p38 Mitogen Activated Protein Kinase;Pathology;patient derived xenograft model;personalized medicine;Pharmaceutical Preparations;Phenotype;Play;pleiotropism;Polysaccharides;polysulfated glycosaminoglycan;predictive marker;Process;Property;prototype;receptor;Receptor Signaling;Regulation;Reproducibility;Reproducibility of Results;Research;Research Personnel;Resources;response;Role;Sampling;scaffold;self-renewal;Serum;Signal Transduction;Site;Specificity;spheroids;Stem Cell Assay;stem cell biology;stem cell biomarkers;stem cell growth;stem cell self renewal;stem cells;System;Testing;Therapeutic;Tissue Sample;Toxic effect;transcriptomics;treatment strategy;tumor growth;Validation;Xenograft Model;Xenograft procedure

PROJECT_TITLE: Unique Non-Saccharide Mimetics of Sulfated Glycosaminoglycan Target Colon Cancer Stem Cells


ORG_CITY: WEST HAVEN

ORG_NAME: VA CONNECTICUT HEALTHCARE SYSTEM

ORG_STATE: CT

PHR: PROJECT NARRATIVE  Chronic kidney disease is a public health problem that affects more than 26 million Americans. We propose to study how histone deacetylase 3 regulates kidney inflammation in chronic kidney disease. Results from our study could provide a new understanding of molecular mechanisms of kidney inflammation and could lead to the development of novel therapeutic strategies for chronic kidney disease.

PI_NAMEs: WANG, YANLIN  (contact)

PROJECT_TERMS: Affect;American;Binding;Cells;chromatin remodeling;Chronic Kidney Failure;cytokine;Deacetylation;Development;DNA;Elements;End stage renal failure;Genetic;genetic approach;HDAC3 gene;Histone Deacetylase;Histone Deacetylase Inhibitor;Histone Deacetylation;Histones;In Vitro;in vivo;Infiltration;Inflammation;Inflammatory;inhibitor;Injury;Injury to Kidney;Kidney;knock-down;Knockout Mice;Macrophage;Macrophage Activation;Mediating;military veteran;Modeling;Molecular;mouse model;Myelogenous;Myeloid Cells;NF-kappa B;novel therapeutic intervention;overexpression;Pathologic;Peptide Initiation Factors;pharmacologic;Population;pre-clinical;Prevalence;prevent;Production;Public Health;Regulation;response;Response Elements;Role;Signal Pathway;Testing;Therapeutic;treatment strategy

PROJECT_TITLE: Targeting histone deacetylase 3 for chronic kidney disease


ORG_CITY: OKLAHOMA CITY

ORG_NAME: OKLAHOMA CITY VA MEDICAL CENTER

ORG_STATE: OK

PHR: Cigarette smoke-induced lung diseases are a major health problem in veterans. Cigarette smoke (CS) suppresses the immune system, and smoking is a major risk factor for chronic obstructive pulmonary disease and respiratory tract infections. We have shown that immunosuppression by CS plays a critical role in the enhanced susceptibility of smokers to serious influenza (IAV) infection. We have also shown that reversing CS- induced suppression of a specific viral sensing pathway prevents CS-induced immunosuppression, restores antiviral responses, and reduces mortality. Here, we will test a novel specific activator of a viral sensing pathway to see if it improves outcomes in model systems of IAV infection. We will also test a new hypothesis for the mechanism of lung injury during IAV infection in a CS-exposure model. Understanding the mechanisms of lung injury during infection and testing new strategies for reversing it in model systems will be important in designing new treatments for preventing and treating IAV infection in veterans.

PI_NAMEs: METCALF, JORDAN PATRICK (contact)

PROJECT_TERMS: Address;Adverse effects;Agonist;Animal Model;Animals;Anti-viral Response;Anti-viral Therapy;Basic Science;Bioinformatics;Biological Models;bronchial epithelium;Cell model;Chemicals;Chronic Obstructive Pulmonary Disease;cigarette smoke;cigarette smoke-induced;cigarette smoke-induced lung disease;cigarette smoking;Clinical;Clinical Research;combustible cigarette;Cytochrome P450;cytokine;Data;Defect;design;Epithelial Cells;Epithelium;experience;experimental study;exposure to cigarette smoke;Family;Genes;Genetic;genetic manipulation;Goals;Health;Human;human model;Immune;Immune response;Immune system;Immunology;Immunosuppression;Impairment;improved;improved outcome;In Vitro;in vivo;Infection;Infection Control;Influenza A virus;influenza infection;Injury;Innate Immune Response;Innate Immune System;innovation;Innovative Therapy;Interferon Activation;Interferon alpha;Interferon Type II;Interferons;Intervention;Ligands;Literature;Lung;lung injury;Mediating;member;Methods;Modeling;mortality;mouse model;Mus;new therapeutic target;non-smoker;novel;overexpression;Pathway interactions;Play;Population;Positioning Attribute;Predisposition;prevent;Production;prophylactic;Proteins;Public Health;pulmonary function;receptor;Respiratory Tract Infections;response;restoration;Risk;Risk Factors;Role;Severities;Signal Transduction;Smoker;Smoking;Smoking treatment;stress reduction;Testing;Therapeutic;Tretinoin;Veterans;Viral;Viral Physiology;Viral Respiratory Tract Infection;Virus Diseases;Work

PROJECT_TITLE: Reversing Cigarette Smoke-Induced Antiviral Immunosuppression


PHR: Acute pancreatitis, an inflammatory disease of the pancreas, is severe in about 25% of patients and causes death in up to 30% of those with severe disease; there is no specific therapy. The most common causes of acute pancreatitis are alcohol abuse, cigarette smoking and gallstones. Since these conditions are more common in our Veterans, the proposed work has strong clinical relevance. Using animal and cellular model of pancreatitis, we have discovered a blood protein (renalase) that protects against pancreatitis, but tends to disappear from blood early in disease. We propose to study renalase for two reasons: 1) It appears to have a strong protective role in pancreatitis and could represent a new therapy, 2) Blood levels of renalase might predict which patients will develop severe disease and also benefit from its use as a therapy.

PI_NAMEs: GORELICK, FRED SANFORD (contact)

PROJECT_TERMS: Acinar Cell;Acute;acute pancreatitis;Affect;Age;Alcohol abuse;alpha 2-Glucoproteins;Animal Model;Antibodies;Appearance;Award;Binding;Binding Proteins;Biological Process;Biology;Blood;Blood Proteins;Calcium;Cause of Death;Cell membrane;Cell model;Cessation of life;Cholelithiasis;cigarette smoking;Clinical;clinically relevant;Complication;Data;Disease;disease natural history;Drug or chemical Tissue Distribution;Excretory function;Exocrine pancreatic insufficiency;Failure;falls;Foundations;Funding;Future;Gastrointestinal Diseases;Gene Expression;Genetic;Hospitalization;Human;Immunoprecipitation;improved;in vivo;Incidence;Individual;Inflammatory;Injury;insight;Kidney;Manuscripts;Mass Spectrum Analysis;Mediating;Mediator;Messenger RNA;military veteran;Modeling;Monitor;mortality risk;mouse model;mRNA Expression;Multiple Organ Failure;Mus;novel;novel therapeutics;Onset of illness;Pancreas;Pancreatic Diseases;Pancreatitis;Patients;Pattern;Phase;Plasma;Plasma Proteins;Population;Prognostic Factor;protective effect;Protein Family;protein purification;protein transport;Proteolysis;Publishing;Pump;Recombinants;reconstitution;Recovery;Regulation;Reporting;Resolution;response;Risk;Role;secretory protein;Serum;Severities;Severity of illness;Source;Testing;Therapeutic;Therapeutic Agents;Time;Tissues;trafficking;uptake;Veterans;Work

PROJECT_TITLE: Regulation of pancreatitis severity


PHR: Project Narrative Antibiotic resistance represents a global problem that impacts multiple areas of medicine and negatively influences the health of all including veterans. The long term focus of this research program has been to understand the molecular mechanisms by which bacterial pathogens, notably the sexually transmitted human pathogen Neisseria gonorrhoeae, resists classical antibiotics and host-derived antimicrobials. Through my research efforts coupled with extensive local, national and international service and teaching/ mentoring tasks I will continue to work to combat the health threat imposed by antibiotic resistant bacterial pathogens that cause serious infections in humans.

PI_NAMEs: SHAFER, WILLIAM MAURICE (contact)

PROJECT_TERMS: Antibiotic Resistance;Antibiotic Therapy;Antibiotics;antimicrobial;Antimicrobial Resistance;Area;Award;Azithromycin;Bacteria;Bacterial Antibiotic Resistance;Bacterial Infections;Basic Science;Biological;Biological Models;career;career development;Cefixime;Ceftriaxone;Cephalosporins;clinical practice;combat;Communicable Diseases;Communities;Country;Coupled;Dedications;Development;Disease;Disease Resistance;doctoral student;Drug Efflux;Education;Educational process of instructing;efflux pump;Faculty;Female;Funding;Funding Agency;Generations;Goals;Gonorrhea;Gynecologic;Health;Homeostasis;Host Defense;Human;human pathogen;improved;Incidence;Infection;Infectious Agent;International;Journals;Knowledge;Laboratories;Leadership;Light;Link;male;Mediator;Medical Research;medical schools;Medicine;meetings;Membrane;Mentors;microbial;Military Personnel;Molecular;Mucous Membrane;Neisseria gonorrhoeae;novel therapeutic intervention;pathogen;Pathogenesis;pathogenic bacteria;Peer Review;Permeability;Pharmaceutical Preparations;Population;Postdoctoral Fellow;pre-doctoral;Predisposition;Productivity;programs;Public Health;Reporting;Research;Resistance;Resistance development;resistance factors;resistant strain;Resources;Science;Scientist;Sepsis;Services;Sexual Transmission;Sexually Transmitted Diseases;Societies;student mentoring;Study Section;Surface;System;therapeutic vaccine;Transcriptional Regulation;Translational Research;translational study;United States;United States National Institutes of Health;Universities;vaccine development;Vaccines;Veterans;Virulence Factors;Work

PROJECT_TITLE: BLRD Research Career Scientist Award Application


ORG_CITY: LOS ANGELES

ORG_NAME: VA GREATER LOS ANGELES HEALTHCARE SYSTEM

PHR: Lung cancer is the leading cause of death among U.S. Veterans. Each year lung cancer exacts a devastating toll in terms of lives lost and resources expended. Recent studies suggest that early metastatic disease may be caused by cells that have an enhanced capacity for rapid movement. This research will identify the mechanisms of rapid cellular movement that underlies early metastatic disease. This will allow the development of new agents that can prevent metastatic activity, thus profoundly shifting the approach to the treatment of lung cancer.

PI_NAMEs: DUBINETT, STEVEN M. (contact)

PROJECT_TERMS: airway epithelium;Antibodies;Behavior;biobank;Biology;biomarker discovery;bronchial epithelium;cancer cell;Cancer Etiology;Carcinoma;Cause of Death;CD8-Positive T-Lymphocytes;Cell Communication;Cell Physiology;Cells;Cessation of life;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;constriction;cytokine;Data;Data Set;Detection;Development;Disease;Disease Progression;Disseminated Malignant Neoplasm;Early Intervention;Epithelial Cells;Epithelium;Event;exosome;Funding;Human;Immunofluorescence Immunologic;Immunosuppression;In Vitro;in vivo;individual patient;innovation;insight;Interferon Type II;Knock-out;Lung;lung cancer cell;lung lesion;Malignant neoplasm of lung;Malignant Neoplasms;Malignant Pleural Effusion;Mediating;Mediator;Mesenchymal;migration;miRNA expression profiling;Motility;Movement;Mutation;Neoplasm Metastasis;New Agents;Non-Small-Cell Lung Carcinoma;Normal Cell;Operative Surgical Procedures;Paracrine Communication;Patients;peripheral blood;Phenotype;physical property;premalignant;Premalignant Cell;prevent;Process;programmed cell death ligand 1;programmed cell death protein 1;Proteins;Proteomics;Reporting;Research;Resources;Time;transcriptomic profiling;United States Department of Veterans Affairs;Veterans;Western Blotting

PROJECT_TITLE: Exosome-mediated mechanisms of metastatic disease in non-small cell lung cancer


ORG_CITY: KANSAS CITY

ORG_NAME: KANSAS CITY VA MEDICAL CENTER

ORG_STATE: MO

PHR: Given the limited efficacy of available therapies in PDAC, a significant focus in PDAC research has been on developing targeted therapies to interfere with the fetal disease effectively. In the proposed research application, we will utilize an iRGD-mediated-hypoxic/pH-responsive nanocarriers (iPRNCs) based therapy. The targeted nano drug will release ZA and uniquely target pancreatic tumors, their microenvironments, and metastatic sites through inhibiting the CYR61-signaling pathway. To that end, the findings of these studies will help in interpreting the results for potential clinical trials of iPRNC-ZA therapy for PDAC.

PI_NAMEs: BANERJEE, SNIGDHA  (contact)

PROJECT_TERMS: 3' Untranslated Regions;Abraxane;Acute;Binding Sites;Biological Availability;Biological Markers;bone;cancer cell;cancer therapy;cell growth;Cell Line;cell motility;Chemopreventive Agent;chemotherapy;Clinical Trials;Desmoplastic;Dose;Down-Regulation;Drug Exposure;Drug Kinetics;Encapsulated;Epithelium;Female;Fetal Diseases;Future;gemcitabine;genetically modified cells;Goals;Growth;Human;Hypoxia;Imaging Techniques;Immunocompetent;improved;In Vitro;in vivo;in vivo imaging;Inbred BALB C Mice;Intravenous;intravenous administration;Invaded;Investigational Drugs;Kidney;KRAS2 gene;Lead;Liver;Luciferases;male;Malignant neoplasm of pancreas;Malignant Neoplasms;Maximum Tolerated Dose;Measures;Mediating;Mesenchymal;Methods;MicroRNAs;migration;Molecular;mortality;mouse model;multidisciplinary;Mus;mutant;nanocapsule;nanocarrier;nanodrug;Neoplasm Metastasis;novel strategies;novel therapeutic intervention;overexpression;Paclitaxel;pancreatic cancer cells;Pancreatic Ductal Adenocarcinoma;pancreatic ductal adenocarcinoma cell;pancreatic ductal adenocarcinoma model;pancreatic neoplasm;patient derived xenograft model;Phenotype;Plasma;Plasmids;Play;Primary Neoplasm;Production;prognostic;Property;Proteins;Regulation;Renal clearance function;Reporter;Research;Resistance;response;Role;Route;Sampling;Signal Pathway;Signal Transduction;Site;Source;spheroids;Spleen;Standardization;targeted treatment;Techniques;Testing;Time;tissue biomarkers;tissue culture;Tissues;Toxic effect;Treatment Efficacy;tumor;tumor growth;tumor progression;Tumor Suppressor Proteins;Ultrasonography;uptake;Veterans;Xenograft procedure;Zoledronic Acid

PROJECT_TITLE: Role of Cyr61/CCN1 in Pancreatic Cancer Progression and Therapy


NIH_SPENDING_CATS: Autoimmune Disease;Digestive Diseases;Inflammatory Bowel Disease

ORG_CITY: DALLAS

ORG_DEPT: PATHOLOGY

ORG_NAME: UT SOUTHWESTERN MEDICAL CENTER

PHR: PROJECT NARRATIVE Current treatments for ulcerative colitis (UC) only address the symptoms or maintain remission of the disease; thus, new prevention and treatment strategies are urgently needed. Targeting long noncoding RNAs (lncRNAs) to treat UC is a promising strategy, as lncRNAs have been associated with intestinal inflammation. The proposed research will identify candidate lncRNAs involved in UC, determine where they are localized in human biopsy samples and mouse models, and elucidate their function and role in disease pathogenesis, leading to new drug targets to alleviate the burden of UC and other intestinal diseases.

PI_NAMEs: GALIA, LIRAZ  (contact)

PROGRAM_OFFICER_NAME: GONDRE-LEWIS, TIMOTHY A

PROJECT_TERMS: Address;Area;Award;Biochemistry;Biological;Biology;Biopsy;Biopsy Specimen;candidate identification;Cells;Cellular biology;cellular imaging;Chronic Disease;Citric Acid Cycle;Colitis;Colon;Complex;Crohn's disease;design;Development;differential expression;Disease;Disease Progression;Disease remission;Distal;Electron Transport;Future;Genetic Transcription;Goals;gut inflammation;Health;Homeostasis;Human;Human Genome;Image;improved;in vivo;Inflammation;Inflammatory;Inflammatory Bowel Diseases;innovation;Intestinal Diseases;intestinal epithelium;intestinal homeostasis;Intestines;Knowledge;Laboratories;Lead;Link;Maps;Massachusetts;medical schools;Metabolic;Metabolic Pathway;Mission;Mitochondria;mitochondrial metabolism;Modeling;Molecular;mouse model;Mus;NADH;National Institute of Allergy and Infectious Disease;Natural Immunity;new therapeutic target;novel;Organelles;Orthologous Gene;Outcome;Oxidative Phosphorylation;Pathogenesis;Patients;Persons;Phenotype;Physiological;Postdoctoral Fellow;Prevention strategy;Production;Proteins;Reactive Oxygen Species;reduce symptoms;Regulation;Research;Resolution;Role;Severity of illness;Shapes;Signal Pathway;Symptoms;Therapeutic;therapeutic development;Tissues;trafficking;Transcript;Translating;treatment strategy;Ulcerative Colitis;Universities;Untranslated RNA;Work

PROJECT_TITLE: Spatial subcellular mapping of the intestinal LncRNAome

STUDY_SECTION_NAME: Special Emphasis Panel[ZAI1 MSA-D (M1)]


ADMINISTERING_IC: AG

IC_NAME: NATIONAL INSTITUTE ON AGING

NIH_SPENDING_CATS: Aging;Bioengineering;Clinical Research

ORG_CITY: Columbus

ORG_NAME: OHIO STATE UNIVERSITY

ORG_STATE: OH

PHR: PROJECT NARRATIVE The accelerated, catastrophic, critical illness-associated form of frailty is an emerging, costly, and age-related public health problem that is driven by the growing number of survivors of critical illness, the aging U.S. population, and the ongoing COVID-19 pandemic. We propose to develop rigorous methods to identify pre- critical illness frailty, which will lead directly to a new generation of clinical interventions to manage and mitigate critical illness-associated frailty and improve long-term health for older adults surviving critical illness. Upon completion of this study, we will have validated questionnaire-based frailty assessments that can be used when performance-based frailty assessments are not possible—an important next step in our work to understand and intervene upon critical illness-associated frailty.

PI_NAMEs: BRUMMEL, NATHAN E (contact)

PROGRAM_OFFICER_NAME: SERRA, MONICA CHRISTINE

PROJECT_TERMS: Acceleration;Admission activity;Affect;age related;Aging;Agreement;American;Automobile Driving;Blinded;Body Weight;Chronic Disease;Clinical;Communities;cost;COVID-19 pandemic;Critical Care;Critical Illness;Data;Data Analyses;disability;Electronics;Enrollment;Ensure;Environment;Etiology;experience;Fatigue;frailty;Funding;Generations;Health;Health Status;Hospitals;improved;infancy;innovation;Intervention;Intervention Trial;Judgment;Knowledge;Lead;Measurement;Measures;Methods;muscle strength;older adult;Outcome;patient population;patient response;Patients;Performance;performance based measurement;Persons;Phenotype;Physical activity;Physical Performance;Population;prevent;Public Health;Questionnaires;Reference Standards;Research;Research Infrastructure;Research Personnel;Respiratory Failure;response;Risk Factors;Shock;sociodemographics;Survivors;Syndrome;Testing;Time;tool;Translating;United States National Institutes of Health;Validity and Reliability;virtual;walking speed;Work

PROJECT_TITLE: Surrogate Assessment of Frailty using Electronic Tools (SAFE-T)

STUDY_SECTION: ASG

STUDY_SECTION_NAME: Aging Systems and Geriatrics Study Section[ASG]


ORG_CITY: PALO ALTO

ORG_NAME: VETERANS ADMIN PALO ALTO HEALTH CARE SYS

PHR: Metastatic breast cancer affects approximately 155,000 Americans, including military active duty women. The goal of this project is to investigate a new tumor suppression pathway implicated in the control of cancer metastasis and recurrence. Successfully completed, this project will validate the importance of this pathway against recurrence of dormant breast cancer, and point the field toward innovative drug discovery strategies for treating metastatic breast cancer.

PI_NAMEs: BIAN, KA  (contact)

PROJECT_TERMS: active duty;Affect;American;Aneuploidy;angiogenesis;Animals;antagonist;Basement membrane;Biological;Biological Models;Breast Cancer cell line;breast cancer metastasis;Breast Cancer Patient;cancer cell;Cancer cell line;Cancer Control;cancer initiation;cancer recurrence;cancer therapy;Cardiovascular system;Categories;Cell Nucleus;Cells;Cyclic GMP;Cyclin-Dependent Kinases;Data;Deterioration;Diagnosis;Distant;Distant Metastasis;DNA Repair;drug discovery;Elements;Endothelium;Enzymes;Epithelial Cells;Extracellular Matrix;G1 Phase;Gene Expression;genome-wide;Glioma;Goals;HDAC3 gene;Histone Deacetylase;Histone Deacetylase Inhibitor;Human;human tissue;Immune;Immune System Diseases;Immunologic Surveillance;Immunological Models;Implant;Individual;Induction of Apoptosis;innovation;Invaded;Malignant Breast Neoplasm;Malignant Neoplasms;Mediating;Metastatic breast cancer;migration;Military Personnel;Modeling;Mus;Neoplasm Circulating Cells;Neoplasm Metastasis;neoplastic cell;Nitric Oxide;Nitrous Oxide;novel;novel therapeutic intervention;Nuclear Translocation;Organ;Pathway interactions;Patients;pharmacologic;Positioning Attribute;Primary Neoplasm;Production;Proliferating;Receptor Signaling;Recurrence;response;Role;Signal Pathway;Signal Transduction;Signaling Molecule;Signaling Protein;Site;Soluble Guanylate Cyclase;Stromal Cells;Surface;Testing;Therapeutic;Time;Tissues;TP53 gene;triple-negative invasive breast carcinoma;tumor;Tumor Suppression;Tumor Suppressor Proteins;Tumor-associated macrophages;Vascular Endothelial Cell;Woman

PROJECT_TITLE: Roll of Nitrous Oxide (NO) and Cyclic GMP in Cancer


ORG_NAME: VA NORTH TEXAS HEALTH CARE SYSTEM

PHR: LAY SUMMARY Myeloid cells are a group of white blood cells that have the capacity to contribute to chronic inflammation in the brain and spinal cord. We recently identified a type of myeloid cell (CD11c+CD88+CD317+ cells) that has not yet been described in the scientific literature, and these cells are associated with accumulation of neurological disability in an animal model of multiple sclerosis (MS). The goal of this proposal is to further understand factors that drive the development of CD11c+CD88+CD317+ cells, with the ultimate objective of designing novel therapies that can counteract them.

PI_NAMEs: STUVE, OLAF  (contact)

PROJECT_TERMS: Adoptive Transfer;Animal Model;Antibody Therapy;Antigen-Presenting Cells;Antigens;Autoantigens;Autopsy;Blood;Blood Vessels;Bone Marrow;Brain;CD4 Positive T Lymphocytes;Cell Adhesion Molecules;Cells;Central Nervous System;Cerebrum;chemokine;chemokine receptor;Chimera organism;Chronic;Clinical;CNS autoimmune disease;CNS autoimmunity;congenic;cytokine;Data;Dendritic Cells;design;Development;Disease;Disease Outcome;draining lymph node;Effector Cell;Experimental Autoimmune Encephalomyelitis;experimental study;Flow Cytometry;Funding;Gene Expression Profile;Genotype;Goals;Growth;Human;Human Resources;Immunize;Immunohistochemistry;In Vitro;Inflammation;Inflammatory;Integrin alpha4;investigator-initiated trial;irradiation;ITGAX gene;Lead;Leukocytes;Literature;Macrophage;Mediator;Meninges;Microglia;Modeling;Molecular;Monoclonal Antibodies;Morphology;Multiple Sclerosis;multiple sclerosis patient;Mus;Myelin;Myeloid Cells;natalizumab;Neurological disability;novel therapeutics;Onset of illness;Outcome;Pathway interactions;Patients;peripheral blood;Phase;Phase IV Clinical Trials;Phenotype;Play;primary lymphoid organ;Procedures;Process;Protein Analysis;PTPRC gene;Recovery;Relapse;Research Personnel;Role;Sampling;secondary lymphoid organ;single-cell RNA sequencing;Site;Spinal Cord;Surface;Testing;therapeutic target;Time;Tissues;transcription factor

PROJECT_TITLE: Defining the role of CD11c+CD88+CD317+ myeloid cells as mediators of CNS autoimmunity


ORG_CITY: LONG BEACH

PHR: PROJECT NARRATIVE  In this pragmatic clinical trial, which will dovetail with Veterans' routine outpatient dialysis clinic visits in six VA medical centers, we will study 252 Veterans with kidney disease who need to start dialysis treatment. If a Veteran is eligible for the study by making enough residual urine, he/she will have a 50% chance to be offered the usual three-times-per-week dialysis vs. twice-per-week dialysis that is gradually increased to three-times- per-week over one year. We will compare health-related quality of life, how long residual kidney function lasts, and other measures including safety in these two groups. By conducting this study, we hope to understand 1) whether starting dialysis with less frequency is safe, effective, and can help Veterans and their care-partners to better cope with dialysis, and 2) if incremental dialysis can result in major cost benefits to the VA health care system, thus allowing more patients to stay in VA dialysis clinics vs. being transferred to outside clinics.

PI_NAMEs: KALANTAR-ZADEH, KAMYAR  (contact);KOVESDY, CSABA PAL;UNRUH, MARK LYNN

PROJECT_TERMS: Address;Adverse event;American;Ancillary Study;arm;Blood Vessels;Cachexia;Cardiac;Cardiovascular system;Caregiver Burden;Caring;Client satisfaction;Clinic;Clinic Visits;Clinical;Clinical Trials;coping;cost;Costs and Benefits;design;Dialysis patients;Dialysis procedure;Dose;Eating;Eligibility Determination;Emergency department visit;End stage renal failure;Event;experience;Fatigue;frailty;Frequencies;functional status;Future;GDF15 gene;Growth;health care service utilization;health related quality of life;Healthcare Systems;Hemodialysis;Hospitalization;Human Resources;hyperkalemia;Hypotension;Hypotensives;Impaired health;improved;indexing;Inflammation;Inflammatory;Injury to Kidney;Intervention;Kidney;Kidney Diseases;Left;Left Ventricular Mass;Life;Longevity;Maintenance;Malnutrition;Measures;Medical center;mortality;mortality risk;Muscle;muscle form;nutrition;Nutritional;Nutritional status;Organ;Outcome;Outcome Measure;Outpatients;Output;Parents;Patient Outcomes Assessments;Patients;physical conditioning;Physical Function;Physical Performance;Population;Pragmatic clinical trial;pragmatic study;precision medicine;preference;preservation;primary endpoint;primary outcome;Proteins;Protocols documentation;Provider;Randomized, Controlled Trials;Regimen;Renal function;Research Design;Research Personnel;Residual state;Resources;Safety;safety assessment;safety outcomes;safety testing;scale up;Schedule;secondary endpoint;secondary outcome;Serum;Site;standard of care;survival prediction;Symptoms;System;Testing;Time;Time trend;Urea;Urine;Veterans;Veterans Health Administration;wasting;Withdrawal

PROJECT_TITLE: Incremental Hemodialysis for Veterans in the First Year of Dialysis (IncHVets): A Pragmatic, Multi-Center, Randomized Controlled Trial


PHR: Systemic lupus erythematosus, or simply lupus, is a chronic disease in which the immune system can attack any organ. More than 90% of patients are women. Our research is investigating why lupus has a predilection for women. Men should have one X and women should have 2. However, our work shows that men with 2 X chromosomes are at the same lupus risk as women, and women with 3 are at an even higher risk for lupus. So, we think that the risk of lupus is related to the number of X chromosomes, not sex. Furthermore, we have identified several genes on the X chromosome that we think may mediate this X chromosome dose effect. This proposal will determine the role of these genes in lupus and the sex bias of the disease. Lupus is a common illness among otherwise healthy young adults. Thus, lupus is frequently diagnosed among military personnel and leads to a medical discharge in most individuals. There are more than 10,000 patients cared for by the VA who are diagnosed with lupus.

PI_NAMEs: SCOFIELD, ROBERT HAL (contact)

PROJECT_TERMS: Affect;Alleles;Aneuploidy;Attention;Autoimmune Diseases;Award;B-Lymphocytes;Binding;Cells;Chronic;Chronic Disease;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;cohort;Communities;Complement;CRISPR/Cas technology;cytokine;Data;Data Reporting;Dendritic Cells;Diagnosis;Disease;Disease remission;Disproportionately impacts women;Distal;Dose;efficacy evaluation;Epidemiology;Female;Flare;Funding;gene interaction;Gene Proteins;Genes;Genetic;Genetic Transcription;genome wide association study;genome-wide analysis;Grant;high risk;Human;Hydroxychloroquine;Immune;Immune system;Impairment;Individual;Inflammatory;Interferons;Interleukin-6;Internet;Klinefelter's Syndrome;knock-down;Lupus;Maintenance;male;Mediating;Medical;men;Messenger RNA;Military Personnel;Molecular;monocyte;Mus;Natural Killer Cells;Organ;Paper;Pathogenesis;Pathway interactions;Patient Care;Patients;Penetration;personalized approach;Pharmaceutical Preparations;Physiological;precision medicine;Primary biliary cirrhosis;Process;Production;Progress Reports;protein expression;Proteins;Publishing;Receptor Signaling;Research;Resources;Rheumatology;Risk;risk variant;Role;Sarcoidosis;Science;Serology;Sex Bias;sex chromosome aneuploidy;Sex Chromosomes;Signal Pathway;Signal Transduction;Sjogren's Syndrome;synergism;Systemic Lupus Erythematosus;T-Lymphocyte;Techniques;Time;TLR7 gene;TNF gene;Toll-like receptors;Translating;Woman;women patients;Work;X Chromosome;X Inactivation;young adult

PROJECT_TITLE: Sex Chromosome Aneuploidies in Autoimmune Disease


PHR: Veterans who are aged and/or diabetic are at major risk for developing difficult non-healing wounds which impact negatively on their ability to achieve a high quality of life as productive members of our society, and the care of these wounds and their sequelae consumes a significant portion of resources within the Veterans Health Administration. To effectively manage these wounds, it is essential to understand the normal healing process, and how that may change with age and diabetes. Our work will improve our understanding of the cells and molecules that control wound healing, how age impacts this process, and will provide insights into how to effectively manage chronic wounds especially in older veterans. The ultimate objective of the research described in this proposal is to develop a solution that allows durable and regenerative healing of these wounds.

PI_NAMEs: HSIA, HENRY C (contact)

PROJECT_TERMS: Ablation;Age;age effect;age related;age related changes;aged;Aging;Binding;Biochemical;cell type;Cells;Cellular Indexing of Transcriptomes and Epitopes by Sequencing;Chronic;chronic wound;Consumption;cytokine;Data;Defect;defined contribution;Deposition;Dermal;Developmental Biology;Diabetes Mellitus;diabetic;Diabetic Foot Ulcer;Diabetic mouse;diabetic patient;diabetic ulcer;Engineering;Environment;experimental study;Extracellular Matrix;Fibroblasts;Genomics;Goals;Growth Factor;healing;Heterogeneity;Human;IGF1 gene;IGF1R gene;improved;In Vitro;in vivo;Infectious Skin Diseases;Injury;insight;Insulin-Like Growth Factor I;Macrophage;member;Mesenchymal;Modality;Modeling;Molecular;Mus;Myofibroblast;neutralizing antibody;non-healing wounds;novel;old mice;Pathologic;Patients;Phenotype;Plastic Surgical Procedures;Population;Process;Productivity;Proliferating;Quality of life;regenerative healing;Regenerative wound healing;repaired;Research;Research Proposals;Resources;response;Risk;Rodent Model;Signal Transduction;single-cell RNA sequencing;Skin;Skin Aging;Skin injury;Skin repair;skin wound;Skin wound healing;Societies;Technology;Testing;therapeutic target;Tissues;Translating;Translational Research;Transplantation;Veterans;Veterans Health Administration;Work;wound;wound bed;wound care;wound healing;wound treatment

PROJECT_TITLE: Defining translational mechanisms to promote regenerative healing of chronic wounds


PHR: Project Narrative: Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide including the United States due to late detection and limited availability of effective long-term therapeutic options. Based on our preliminary observation, the current proposal seeks to determine at a molecular level whether a signaling protein called Mixed Lineage Kinase 3 (MLK3) promotes HCC while also providing a mechanistic insight towards the downstream events involved in mediating these. Successful outcome of our study will reveal whether pharmacological targeting of MLK3 can be used as a potential therapeutic strategy to combat HCC.

PI_NAMEs: RANA, BASABI  (contact)

PROJECT_TERMS: antagonist;Apoptosis;Apoptotic;Attenuated;BAY 54-9085;beta catenin;Biochemical;Biological;Biological Assay;Breast;Cancer Etiology;carcinogenicity;Carcinogens;Cause of Death;Cell Cycle Arrest;Cell Survival;Cells;CEP 1347;Cessation of life;chemokine;Colorectal Cancer;combat;cytokine;Cytokine Signaling;Data;Death Rate;design;Detection;Development;Event;Family;Family member;Feedback;Future;Gene Expression;Gene Expression Profile;Genetic Models;Goals;Hepatocarcinogenesis;Human;IL6 gene;Immunohistochemistry;in vivo;Inflammatory;inhibitor;insight;Interleukin-1 beta;Interleukin-11;Interleukin-6;knock-down;Knockout Mice;Link;Liver;liver cancer model;Malignant Epithelial Cell;Malignant neoplasm of gastrointestinal tract;Malignant neoplasm of liver;Malignant Neoplasms;MAP Kinase Gene;MAPK8 gene;Mediating;member;Mitogen-Activated Protein Kinase Kinases;mixed lineage kinase 3;Modeling;Molecular;mouse model;Mus;Nodule;novel;Oncogenic;Outcome;Outcome Study;overexpression;Pharmaceutical Preparations;pharmacologic;Phosphotransferases;pre-clinical;preclinical efficacy;Primary carcinoma of the liver cells;Proliferating;RAS genes;Reporting;Role;Sampling;Signal Pathway;Signal Transduction;Signaling Molecule;Signaling Protein;Stains;Stomach;Therapeutic;Therapeutic Intervention;therapeutically effective;Tissue Microarray;TNF gene;tumor;tumor progression;United States;Up-Regulation;upstream kinase;Wild Type Mouse

PROJECT_TITLE: Mixed Lineage Kinase 3 and cytokine signaling axis in hepatocellular carcinoma


ORG_CITY: PORTLAND

ORG_NAME: PORTLAND VA MEDICAL CENTER

ORG_STATE: OR

PHR: Project Narrative: The research program broadly investigates substance use disorders. One project explores the causes of, and treatments for the specific effects of the synthetic opioid, fentanyl, as opposed to the opioid morphine, the active metabolite of heroin. Opioid deaths are 7-fold greater among veterans than they are in the general population, and deaths due to fentanyl have risen to record levels while deaths due to heroin have nearly plateaued. Naloxone reverses symptoms of heroin overdose, but is far less effective in treating fentanyl overdose. We are developing new medications specific to fentanyl’s unique toxic effects. We are also investigating differences we found between methamphetamine-abusing human subjects and control subjects in the cargo of vesicles released by cells. We are examining the differences across other neuropsychiatric disorders, and are determining how they can be used to develop new treatments.

PI_NAMEs: JANOWSKY, AARON J. (contact)

PROJECT_TERMS: addiction;Address;Admission activity;Adrenergic Receptor;Affect;Aging;analog;Animal Model;animal tissue;Antipsychotic Agents;Award;Binding;Biological Assay;career;Cells;Central Nervous System;Cessation of life;Clinical;Clinical Treatment;Cocaine Abuse;commercialization;comorbidity;computational chemistry;Computer Models;Data;Development;Diagnosis;Disease;Dose;Drug abuse;Drug Modelings;Drug Receptors;Engineering;Etiology;experience;extracellular vesicles;FDA approved;Fentanyl;fentanyl overdose;Friends;G-Protein-Coupled Receptors;General Population;Genetic;Genetic Polymorphism;Goals;Heroin;heroin overdose;Hospitals;Human;human disease;human model;human subject;human tissue;Image;improved;In Vitro;in vivo;individualized medicine;interest;Ion Channel;Laboratories;Mediating;Medical;Mental Depression;Mental disorders;Mental Health;Methamphetamine;methamphetamine abuse;Methods;microRNA delivery;MicroRNAs;military veteran;Mission;model development;Modification;molecular modeling;Morphine;mu opioid receptors;Naloxone;naloxone dispensing;neurochemistry;neuropsychiatric disorder;neurotransmitter release;neurotransmitter uptake;Neurotransmitters;novel;novel therapeutics;Opioid;opioid abuse;opioid mortality;opioid overdose;opioid use disorder;Outpatients;Overdose;Patient Care;Patients;Pharmaceutical Preparations;pharmacologic;Pharmacology;Pharmacotherapy;Post-Traumatic Stress Disorders;programs;Proteins;Protocols documentation;Psychotic Disorders;Publications;Publishing;radioligand;Reagent;receptor;Recombinant Proteins;Recombinants;Recurrence;Reporting;Research;response;Schizophrenia;Scientist;screening;Second Messenger Systems;Services;Signal Transduction;Sleep Apnea Syndromes;Substance Use Disorder;symptomatic improvement;Symptoms;synthetic opioid;System;Therapeutic;Toxic effect;treatment adherence;United States Department of Veterans Affairs;Ventilatory Depression;vesicular monoamine transporter;vesicular release;Veterans;Veterans Health Administration;vocal cord;Wakefulness;Work

PROJECT_TITLE: BLRD Senior Research Career Scientist Award Application


ORG_CITY: Aurora

ORG_NAME: VA EASTERN COLORADO HEALTH CARE SYSTEM

PHR: Bacterial infections are a major public health burden and antibiotic resistant bacteria are increasingly difficult to treat with available drugs. Antibiotic development is stagnant and new classes of drugs are desperately needed. Methicillin resistant Staphylococcus aureus (MRSA) and tuberculosis are a major global concern and disproportionately affect Veterans. Tuberculosis is endemic to many regions with a regular military presence, and MRSA is rampant in VA hospitals at home with treatments being costly and often ineffective. Both military occupational exposures and clinical burdens are a CSR&D priority research area. This proposal aims to develop new drugs against novel bacterial mechanisms and establish Dr. Wlodarchak as a translational VA scientist in drug discovery and development. Successful completion of this work will have a positive benefit on understanding how these drugs act on novel bacterial targets and provide drugs for further clinical development. This is an important step to reduce the burden of these diseases on Veteran health.

PI_NAMEs: WLODARCHAK, NATHAN J (contact)

PROJECT_TERMS: Actinobacteria class;Affect;American;Antibiotic Resistance;antibiotic resistant infections;Antibiotics;Area;Award;Bacterial Antibiotic Resistance;Bacterial Infections;beta-Lactam Resistance;beta-Lactams;Binding;Biochemical;Biological;burden of illness;career;cell growth;Cell Wall;Cells;cellular transduction;Chemicals;Clinical;clinical development;Clinical Treatment;clinically relevant;combat;Complement;cost;Data;design;Developing Countries;Development;Disease;drug action;Drug Design;drug development;drug discovery;Drug Targeting;environmental change;Family;Firmicutes;FLT3 gene;Future;Genetic;Genus Mycobacterium;Goals;Growth;Health;Healthcare;Healthcare Systems;Home;Homeostasis;Hospitalization;Hospitals;Human;improved;in vivo;India;Infection;inhibitor;insight;kinase inhibitor;Knock-out;Lead;Mediating;Membrane;Mentors;Metabolism;methicillin resistant Staphylococcus aureus;Middle East;Military Personnel;Multi-Drug Resistance;Mycobacterium Infections;Mycobacterium tuberculosis;new therapeutic target;Nocardia;Nosocomial pneumonia;novel;novel drug class;novel strategies;novel therapeutics;Occupational Exposure;Organism;Outcome;pathogen;Pathway interactions;Patients;Penicillins;Persons;Pharmaceutical Preparations;pharmacologic;phosphatase inhibitor;phosphoproteomics;Phosphoric Monoester Hydrolases;Phosphorylation;Phosphotransferases;Post-Translational Protein Processing;Predisposition;Process;programs;protein expression;Protein Kinase;Protein phosphatase;Proteins;Proteomics;Public Health;Quality of life;rational design;Research;Research Personnel;Research Priority;Resistance;Resistance development;resistance factors;resistance mechanism;resistant strain;Resources;response;Scientist;Series;Serine;Serine/Threonine Phosphorylation;Signal Transduction;skills;Southeastern Asia;Staphylococcus aureus;Staphylococcus aureus infection;Stress;Structure;Structure-Activity Relationship;synergism;System;Techniques;Testing;Threonine;Time;Toxic effect;Training;trait;transcriptome sequencing;transcriptomics;translational scientist;Treatment Failure;Tuberculosis;United States National Institutes of Health;Vancomycin Resistance;Veterans;Veterans Health Administration;Virulence;Work

PROJECT_TITLE: Targeting Bacterial Signaling Cascades as a Novel Antibiotic Strategy


ORG_CITY: SAN ANTONIO

ORG_NAME: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM

PHR: A recent report on 7 million VA patients showed that more than 52% of them have chronic kidney disease (CKD). Diabetes is one of the most prevalent chronic diseases among people aged 18 years and older in the US. Nearly 27% of people in the age group of 65 years or older, that falls in the demographics of Veteran population, have diabetes. Diabetic nephropathy is the leading cause of end stage kidney disease accounting for about half of the cases. Furthermore, a study in Veterans with diabetes and CKD showed that more than 50% patients die or on dialysis after 5 years of follow-up. Diabetes also acts as a risk factor for renal cancer. Current therapies only delay the progression of diseases and do not arrest them. Thus, there is an urgent need for new therapy. We interrogate the molecular signaling events that drive the pathologies and provide new therapeutic strategies for these diseases. Our studies will help identifying drugs that can lead to alleviating the burden of diabetes-associated kidney disease and kidney cancer.

PI_NAMEs: GHOSH CHOUDHURY, GOUTAM  (contact)

PROJECT_TERMS: 18 year old;Accounting;age group;Albuminuria;American;Applications Grants;Award;Businesses;cardiovascular risk factor;care seeking;career;Caring;Categories;Cells;Chromosome 10;Chronic Disease;Chronic Kidney Failure;Clinical;Collagen;Complex;Complications of Diabetes Mellitus;cost;Death Rate;demographics;Diabetes Mellitus;diabetic;Diabetic mouse;Diabetic Nephropathy;diabetic patient;diabetic rat;Dialysis procedure;Disease;Disease Progression;Down-Regulation;End stage renal failure;Enhancers;Epigenetic Process;Epithelial Cells;Event;Exhibits;falls;Fibronectins;Fibrosis;follow-up;Follow-Up Studies;Foundations;FRAP1 gene;Glucose;Goals;Grant;Grant Review;Healthcare;high risk;Homologous Gene;Human;human old age (65+);Hyperglycemia;Hypertrophy;Individual;inhibitor;innovation;International;Invaded;Investigation;Kidney;Kidney Diseases;Kidney Failure;kidney fibrosis;Malignant Epithelial Cell;Malignant Neoplasms;Mediating;Medical;Medicare;member;men;MicroRNAs;military veteran;Mission;Molecular;Monitor;Morbidity - disease rate;mortality;Mus;non-diabetic;novel;novel therapeutic intervention;novel therapeutics;Outcome;pandemic disease;Pathologic;Pathology;Patients;Persons;Pharmaceutical Preparations;Phosphotransferases;Platelet-Derived Growth Factor Receptor;Polycomb;Population;Prevalence;Proliferating;protein expression;Proteins;PTEN gene;Publishing;Regulation;Renal Carcinoma;Renal Cell Carcinoma;Renal Replacement Therapy;Renal Tissue;Reporting;Repressor Proteins;Research;Research Project Grants;response;Retrospective Studies;Review Committee;Risk Factors;Rodent;Rodent Model;Role;scientific organization;Scientist;Signal Transduction;Signaling Molecule;Sirolimus;Study Section;System;Testing;Therapeutic;therapeutic miRNA;Time;Transforming Growth Factors;Translating;Trust;Tubular formation;Tumor Suppressor Proteins;Type 2 diabetic;United States National Institutes of Health;Veterans;Work