PHR: The proposed research is relevant to public health because it will advance our understanding of the pathogenic mechanism of pancreatitis, a disease with considerable morbidity and mortality and currently without a treatment. This disease is common in Veterans, as well as non-Veterans, patient population. Our studies indicate that dysfunctions of cellular organelles, such as lysosomes, mitochondria and the autophagic compartment, are central to disease initiation and progression. The published and proposed studies provide mechanistic insight into pancreatic cell organelle disorders, with the focus on their inter-relations and the pathways linking these disorders to pancreatitis pathologies such as inflammation and cell death. The results identify molecular targets amenable for pharmacologic intervention to normalize organellar functions and reduce pancreatitis severity. Thus, this proposal is highly relevant to the goal of VA Medical Research to develop novel strategies for pancreatitis treatment based on elucidation of the disease mechanism.

PI_NAMEs: GUKOVSKAYA, ANNA S. (contact)

PROJECT_TERMS: Achievement;Acinar Cell;acute pancreatitis;Alcohol abuse;Alcoholic Pancreatitis;Alcohols;American;Automobile Driving;Autophagocytosis;Award;Bibliography;Biochemistry;Book Chapters;California;care costs;career;Cause of Death;Cell Death;Cells;Cellular Metabolic Process;Cholesterol;Cholesterol Homeostasis;chronic pancreatitis;cigarette smoke;clinical investigation;clinically relevant;Collaborations;Databases;Digestive System Disorders;Disease;drug development;editorial;Educational workshop;effective therapy;Endoplasmic Reticulum;endoplasmic reticulum stress;Environmental Risk Factor;Enzymes;Excision;Exocrine pancreas;Functional disorder;Funding;Gastroenterology;Gastrointestinal Diseases;Genetic;genetic approach;Goals;Grant;Healthcare Systems;high risk;Hospitalization;Human;human old age (65+);Impairment;improved;indexing;Inflammation;Inflammatory;Inflammatory Response;insight;Institution;interest;Internet;Intervention;Journals;Knowledge;Link;Los Angeles;Lysosomes;Malignant neoplasm of pancreas;Manuscripts;Mediating;Medical center;Medical Research;medical schools;Medicine;Mitochondria;mitochondrial dysfunction;mitochondrial permeability transition pore;Modeling;Molecular;Molecular Target;Morbidity - disease rate;mortality;mouse model;Mutation;National Institute of Diabetes and Digestive and Kidney Diseases;National Institute on Alcohol Abuse and Alcoholism;necrotic tissue;Non-Malignant;novel;novel strategies;novel therapeutic intervention;Organelles;Pancreas;Pancreatic Adenocarcinoma;Pancreatic Diseases;Pancreatitis;Paper;Participant;Pathogenesis;Pathogenicity;Pathology;Pathway interactions;Patient Care;patient population;Peer Review;Pharmaceutical Preparations;pharmacologic;Physiological;Physiology;Positioning Attribute;professor;Program Research Project Grants;programs;Proteins;Public Health;Publications;Publishing;Quality of life;Recommendation;Research;residence;Resistance;response;Risk;Risk Factors;Role;Science;Scientist;Severities;Signal Pathway;Signal Transduction;Site;Smoking;SPINK1 gene;Survival Rate;symposium;trafficking;translational approach;treatment strategy;United States;United States National Institutes of Health;Universities;Veterans;Work


ADMINISTERING_IC: VA

ARRA_FUNDED: N

FUNDING_MECHANISM: NON-SBIR/STTR RPGS

IC_NAME: Veterans Affairs

ORG_CITY: RICHMOND

ORG_COUNTRY: UNITED STATES

ORG_FIPS: US

ORG_NAME: VA VETERANS ADMINISTRATION HOSPITAL

ORG_STATE: VA

PHR: Elderly Veterans suffer a high incidence of coronary artery disease that can lead to heart attacks. During a blocked artery heart attack, elderly patients unfortunately sustain greater heart damage compared to younger patients. This disparity persists despite successful treatment of the heart attack with rapid restoration of blood flow back to the heart muscle. Our research found that the aged heart is intrinsically more susceptible to injury during a heart attack. This increased risk is due to dysfunctional mitochondria, the “powerhouses” of the heart cell. During a heart attack, these deranged mitochondria cause more heart cell death. Our research has provided key insights in to the causes of the mitochondrial dysfunction, and in preclinical studies we have identified treatments to potentially reverse the aging dysfunction. Initial work supports that when aged hearts have the dysfunction reversed, they suffer less heart injury. We propose that treatment of the aging mitochondrial dysfunction in elders can preemptively decrease injury from a subsequent heart attack.

PI_NAMEs: LESNEFSKY, EDWARD J (contact)

PROJECT_TERMS: 5'-AMP-activated protein kinase;Acceleration;Acute;Adult;Age;age related;aged;Aging;aging mechanism;aging reversal;attenuation;Back;biological adaptation to stress;Blood flow;Calcium;Calpain;Cardiovascular Diseases;Cell Death;cell growth;Cellular Stress;Chronic;clinically relevant;Complex;Coronary Arteriosclerosis;Coronary artery;Cytosol;Defect;Disparity;Down-Regulation;Elderly;Electron Transport;Endoplasmic Reticulum;endoplasmic reticulum stress;Excision;feeding;FRAP1 gene;Functional disorder;Genes;Heart;heart cell;heart damage;Heart Diseases;Heart failure;Heart Injuries;Impairment;improved;Incidence;Injury;insight;insulin signaling;Intervention;Ischemia;ischemic injury;Lead;Link;Mediating;Membrane;Metabolic;Metabolic stress;Metformin;military veteran;Mitochondria;mitochondrial dysfunction;Myocardial Infarction;myocardial injury;Myocardium;novel;old mice;older patient;Oxidative Phosphorylation;pathological aging;Patients;Peptide Hydrolases;preclinical study;Predisposition;Production;programs;Protein Biosynthesis;Protein Complex Subunit;Protein Kinase;Proteins;Reactive Oxygen Species;Reperfusion Therapy;Research;restoration;Risk;Role;Scheme;Signal Transduction;Stress;Structure;Therapeutic;translational potential;Up-Regulation;Veterans;Work

PROJECT_TITLE: Mitochondrial Dysfunction in the Aged Heart:  Role of Endoplasmic Reticulum Stress


FUNDING_MECHANISM: OTHERS

ORG_CITY: SAN FRANCISCO

ORG_NAME: VETERANS AFFAIRS MED CTR SAN FRANCISCO

ORG_STATE: CA

PHR: Our research focusing on new therapeutics for Neisseria gonorrhoeae infection is highly relevant to the U.S. military and Veterans. Cases of gonorrhea are a major cause of morbidity with an estimated 850,000 cases in the U.S. and 87 million cases worldwide. Within the VA Health Care System, the incidence of gonorrhea increased between 2013 and 2017 with the total number of cases at 10,587. There is no vaccine to N. gonorrhoeae and a great need for new antibiotics due to the alarming rise in multidrug resistant strains, which is making emergence of untreatable gonococcal infections a real prospect. The high-risk environment of active military service is thought to increase risky behavior and, thus, the rate of sexually transmitted infections. Military and Veteran females, who incur a rate of gonorrhea that is higher than for civilian females and who suffer more frequent and serious complications than men, represent 15% of active duty military personnel and 2 million Veterans. Thus, our proposed research is relevant to the health and patient care missions of the VA.

PI_NAMEs: JARVIS, GARY A (contact)

PROJECT_TERMS: active duty;Afghanistan;Amino Acids;Anabolism;Antibiotics;Antigens;antimicrobial;Antimicrobial Cationic Peptides;Award;bactericide;California;Cardiovascular system;career;Cells;Cervical;Classification;Collaborations;Communicable Diseases;Community Participation;cytokine;cytotoxicity;Data;design;Development;Disease;Drug Kinetics;Education;Engineering;Environment;Enzymes;Epithelial Cells;Faculty;Family;Female;Funding;Funding Agency;Gonorrhea;Growth;Healthcare;Healthcare Systems;high risk;high risk population;Human;Human Resources;Immune;Immune response;In Vitro;in vivo;in vivo evaluation;Incidence;Infection;Inflammation;Inflammatory;inhibitor;Innate Immune System;International;Invaded;Investigation;Iraq;Journals;Lead;Lipid A;lipid biosynthesis;male;Measurable;Mediating;Membrane;men;Mentors;Military Personnel;military service;Mission;Modeling;Morbidity - disease rate;mouse model;Multi-Drug Resistance;Neisseria;Neisseria gonorrhoeae;Neisseria meningitidis;neutrophil;novel;novel therapeutics;Outcome;Patient Care;patient population;Peer Review;Penetration;Peptides;phosphoethanolamine;Phosphorylation;Positive Test Result;Postdoctoral Fellow;prevent;programs;Public Health;Reporting;reproductive tract;Research;Research Personnel;resistant strain;Risk Behaviors;Role;San Francisco;Scientist;service member;Services;Severities;Sexually Transmitted Diseases;small molecule inhibitor;Students;Surveys;symposium;Testing;Therapeutic;therapeutic target;Time;Toxic effect;Transferase;Translation Initiation;translational study;United States Preventative Services Task Force;Universities;Vaccines;Variant;Vesicle;Veterans;Virginia;Virulence;Western Australia;Woman;Work

PROJECT_TITLE: BLRD Research Career Scientist Award Application


ORG_CITY: Decatur

ORG_NAME: VETERANS HEALTH ADMINISTRATION

ORG_STATE: GA

PHR: Non-Alcoholic Fatty liver disease is a major health problem for veterans. It involves the accumulation of fat in the liver known as hepatic steatosis. It is seen in obese patients. Glial cell line-derived neurotrophic factor (GDNF) may play an important role in the prevention or treatment of hepatic steatosis. Experiments outlined in this proposal will study the mechanism of how GDNF regulates hepatic steatosis. These experiments will not only contribute to the understanding of the mechanisms of regulation of hepatic steatosis, but may also lead to new therapeutic targets for its prevention and treatment. Impact on Veterans Health Care: Hepatic steatosis is highly prevalent in the Veteran population and the incidence is rising. Results from this study can help veterans by identifying new targets to prevent and treat obesity related liver diseases like steatosis.

PI_NAMEs: SRINIVASAN, SHANTHI K (contact)

PROJECT_TERMS: Apoptosis;Autophagocytosis;Biogenesis;Cell Death;cell injury;chronic liver disease;cost;CREB1 gene;Data;Development;drinking water;Eating;experimental study;Fatty acid glycerol esters;Fatty Liver;Fibrosis;Fructose;Genes;Genetic;Ginger;glial cell-line derived neurotrophic factor;Glial Fibrillary Acidic Protein;Glucose;Health;Healthcare;Healthcare Systems;Hepatic;Hepatocyte;High Fat Diet;Human;improved;In Vitro;in vivo;Incidence;knock-down;Knockout Mice;lipid nanoparticle;Lipids;Liver;Liver Fibrosis;liver injury;Mediating;Metabolic syndrome;military veteran;Mitochondria;Mus;nanoparticle;Neuroglia;neurotrophic factor;new therapeutic target;non-alcoholic fatty liver disease;novel;obese patients;Obesity;Obesity associated liver disease;Obesity Epidemic;overexpression;Overweight;Palmitates;Pathway interactions;Patients;pharmacologic;Physical activity;PINK1 gene;Play;pleiotropism;Prevalence;prevent;Prevention;promoter;protein expression;Publishing;receptor;Regulation;Reporting;Role;Signal Pathway;Signal Transduction;stellate cell;Testing;Tissues;Transgenic Mice;Veterans;western diet;Wild Type Mouse

PROJECT_TITLE: Mechanism of GDNF Regulation of Hepatic Steatosis


ORG_CITY: OKLAHOMA CITY

ORG_NAME: OKLAHOMA CITY VA MEDICAL CENTER

ORG_STATE: OK

PHR: Project Narrative Pancreatic cancer (PC) has the highest mortality of any cancer, including in US Veterans, with a low 5-year survival rate. Despite progress in the development of targeted therapies, the survival rate remains unacceptably low. It is, therefore, important to identify novel therapeutics for the treatment of pancreatic cancer patients. This proposal is built on the novel concept that pancreatic tumors produce high levels of mucins, which promote the tumor growth and limit the therapeutic effects. We discovered that the Core2 mucin synthesis gene is overexpressed and responsible for various subtypes of mucins. We identified talniflumate as a novel inhibitor of the Core2 gene. In this proposal, we establish talniflumate as the inhibitor of pancreatic tumor growth and the combining of therapeutic drugs, gemcitabine + nab-paclitaxel, may significantly improve therapeutic efficacy. The results obtained from this study will have high impact and be highly translational in nature.

PI_NAMEs: RAO, CHINTHALAPALLY V. (contact)

PROJECT_TERMS: Ablation;Address;Adenocarcinoma;Anabolism;Binding;cancer therapy;Carcinoma;Cell Physiology;Chemoresistance;chemotherapy;Clinical Research;clinical translation;clinically relevant;Clustered Regularly Interspaced Short Palindromic Repeats;Combined Modality Therapy;Development;Disease;Docking;Dose;Drug Delivery Systems;Duct (organ) structure;effective therapy;efficacy evaluation;Enzymes;Family;Future;gemcitabine;gene synthesis;Genes;Genetic;Genetic Engineering;Growth;Health;Human;human data;Impairment;improved;in silico;In Vitro;in vivo;Incidence;inhibitor;Investigation;knock-down;Knock-out;KPC model;Lesion;male;Malignant - descriptor;Malignant neoplasm of pancreas;Malignant Neoplasms;Mediating;Methods;Molecular;mortality;MUC5AC gene;Mucin 1 protein;Mucin-2 Staining Method;Mucins;Mus;N-Acetylglucosaminyltransferases;Nature;Neoplasm Metastasis;Neoplasms;neoplastic;neoplastic cell;next generation sequencing;novel;novel strategies;novel therapeutic intervention;novel therapeutics;Oncogenic;Outcome;overexpression;Paclitaxel;Pancreas;pancreatic cancer cells;pancreatic cancer patients;Pancreatic Intraepithelial Neoplasia;pancreatic neoplasm;pancreatic PDX models;Pathogenesis;patient derived xenograft model;Patients;Pharmaceutical Preparations;pharmacologic;Pharmacotherapy;Positron-Emission Tomography;preclinical study;Production;Proliferating;Property;Research;Resistance;response;Role;Signal Pathway;Signal Transduction;simulation;Site;Slice;Small Interfering RNA;Source;spheroids;Survival Rate;targeted treatment;Testing;Therapeutic;Therapeutic Effect;therapeutic target;Tissues;transcriptome sequencing;translational approach;Treatment Efficacy;treatment response;treatment strategy;tumor;tumor growth;tumor progression;Tumor Promotion;Tumor Tissue;Tumor Weights;tumor xenograft;tumorigenesis;Up-Regulation;uptake;Veterans;whole genome;women patients;Xenograft procedure

PROJECT_TITLE: Targeting GCNT3 for Pancreatic Cancer


ORG_CITY: HOUSTON

ORG_NAME: MICHAEL E DEBAKEY VA MEDICAL CENTER

ORG_STATE: TX

PHR: Pulmonary hypertension (PH) is caused by narrowing and contraction of the small blood vessels of the lung, leading to irreversible heart failure. PH most commonly occurs in patients with advanced heart and lung disease and is disproportionately more prevalent in veterans compared to other populations. As PH has no cure, we need to understand the causes of lung vessel narrowing and contraction to design better treatments for PH. This project will try to understand how the movement of potassium and calcium ions in and out of cells that line the lung blood vessels control how these blood vessel contract and relax, and how blood vessels become irregularly narrowed, inhibiting blood flow in the lungs. Understanding the factors that control potassium and calcium in these cells will promote the discovery of targeted new drugs to benefit patients suffering from PH.

PI_NAMEs: PANDIT, LAVANNYA M. (contact)

PROJECT_TERMS: Affect;Anatomy;Arteries;Binding;Blood flow;Blood Vessels;Cadaver;Calcium;Calcium ion;Calmodulin;Candidate Disease Gene;candidate identification;Cell Line;Cell membrane;Cell Physiology;Cell Separation;Cells;Cellular biology;Characteristics;college;Confocal Microscopy;constriction;Contracts;density;design;Development;Diameter;Disease;Distal;effective therapy;Elasticity;Endothelin Receptor;Endothelin-1;Exhibits;Experimental Genetics;experimental study;Family;Family member;Fibrosis;fibrotic lung disease;Five-Year Plans;Functional disorder;Gene Expression;gene interaction;Genes;Genetic;Growth;Health Sciences;Heart Diseases;Heart failure;Heterogeneity;Human;human tissue;Hypertrophy;idiopathic pulmonary fibrosis;In Situ;Inherited;Institution;interest;Ion Channel;K-Series Research Career Programs;knock-down;Knockout Mice;Knowledge;Lesion;Ligands;Link;Lobar;Location;Lung;Lung Diseases;Lung Transplantation;Maps;Measures;Medial;Medical center;Medicine;Membrane Potentials;Micro Array Data;Microanatomy;microscopic imaging;Modeling;Modification;mouse model;Movement;Muscle;Muscle Contraction;new therapeutic target;non-smoking;overexpression;Pathologic;Pathway interactions;Patients;pharmacologic;Play;Population;Potassium;Potassium Channel;potassium ion;preference;Proliferating;pulmonary arterial hypertension;Pulmonary artery structure;Pulmonary Fibrosis;Pulmonary Hypertension;pulmonary vascular cells;pulmonary vascular remodeling;Pulmonary vessels;Radiolabeled;Radioligand Assay;receptor;Receptor Cell;Regional Anatomy;Relaxation;Research;Resistance;Rest;restoration;right ventricular failure;Risk;RNA;Role;Sampling;Sarcoplasmic Reticulum;Signal Transduction;Site;Smooth Muscle Myocytes;Structure of parenchyma of lung;Survival Rate;Testing;Texas;thrombotic;Thromboxane Receptor;trafficking;United States Department of Veterans Affairs;Universities;vascular bed;Vascular Diseases;Vascular remodeling;Vascular Smooth Muscle;vascular smooth muscle cell proliferation;vasoconstriction;Vasoconstrictor Agents;Veterans;Work

PROJECT_TITLE: Anatomic microniches and their contribution to vascular remodeling in pulmonary hypertension


ORG_CITY: CLEVELAND

ORG_NAME: LOUIS STOKES CLEVELAND VA MEDICAL CENTER

ORG_STATE: OH

PHR: The goal of this proposal is to investigate possible contributions of skeletal muscle Swedish mutant amyloid precursor protein (APPswe) to the pathogenesis of Alzheimer’s disease (AD). The results will reveal novel links of muscular APPswe with sarcopenia and/or AD brain pathology, a prerequisite to develop better diagnosis and therapeutic intervention for both AD and sarcopenia that occur at higher rate among veterans.

PI_NAMEs: XIONG, WEN-CHENG  (contact)

PROJECT_TERMS: Acceleration;Actins;Action Potentials;Adult;Affect;Age;age-related disease;Alzheimer's Disease;Alzheimer's disease brain;Alzheimer's disease model;Alzheimer's disease pathology;Alzheimer's disease patient;Alzheimer's disease risk;Amyloid;Amyloid beta-Protein Precursor;Animal Disease Models;Behavior;Blood Circulation;Body Weight decreased;Brain;brain cell;Brain Pathology;CCL1 gene;CDKN2A gene;Cell Aging;cell growth;cell type;Cells;cerebrovascular amyloid;chemokine;Chronic;Cognitive deficits;CXCL13 gene;CXCL2 gene;cytokine;Defect;Dementia;Denervation;Development;Diagnosis;Disease Progression;Early Onset Alzheimer Disease;Encephalitis;Exhibits;Galactosidase;Genes;genetic risk factor;Gliosis;Goals;Growth Factor;hepcidin;Hippocampus;Homeostasis;Human;IL6 gene;Impairment;Inflammation;Inflammatory;Iron;Late Onset Alzheimer Disease;Light;Link;LoxP-flanked allele;Maintenance;Mental Depression;Metabolism;mouse model;Mus;Muscle;muscle aging;Muscle Cells;muscle degeneration;muscle form;Muscle function;muscle strength;Muscle Weakness;muscular structure;mutant;Mutation;Neurofibrillary Tangles;neurogenesis;Neuroglia;Neuromuscular Junction;neuron loss;novel;Pathogenesis;Pathogenicity;Pathologic;peptide hormone;Phenotype;Plasma;Population;Process;promoter;Research;risk variant;Role;sarcopenia;selective expression;senescence;senescence associated secretory phenotype;senescent cell;Senile Plaques;Serum;Severities;skeletal;Skeletal bone;Skeletal Muscle;skeletal muscle wasting;tau-1;Testing;Tg2576;Therapeutic Intervention;Thinness;Time;Tissues;TP53 gene;Transfection;Transgenes;Transgenic Mice;Veterans

PROJECT_TITLE: Skeletal Muscular Swedish Mutant APP in Alzheimer's Disease Development


ORG_CITY: IOWA CITY

ORG_NAME: IOWA CITY VA MEDICAL CENTER

ORG_STATE: IA

PHR: The current proposal is directly relevant to the health of U.S. military veterans because it will investigate mechanisms involved in the detrimental actions of activating nicotinic receptors, leading to the development of hypertension. Hypertension is a significant risk factor for cardiovascular disease. Nicotine use, hypertension, and cardiovascular disease are highly prevalent among veterans. Nicotine selectively leads to the development of hypertension in a subset of patients. The receptors that bind nicotine, can also be activated by endogenous molecules such as acetylcholine, a neurohormonal molecule present in the body. Results from this study will identify the receptor involved in nicotine-mediated hypertension, inflammation, and determine whether endogenous acetylcholine activates nicotinic receptors, leading to the development of hypertension. Determining the ability of acetylcholine to trigger the development of hypertension through a particular nicotinic receptor will lead to new therapies that will directly benefit the veteran population.

PI_NAMEs: HARWANI, SAILESH  (contact)

PROJECT_TERMS: Acetylcholine;Adrenergic Agents;Adult;Affect;Agonist;Anti-Hypertensive Agents;arm;Autonomic nervous system;Basic Science;Blood Pressure;Cardiovascular Diseases;cardiovascular risk factor;Cardiovascular system;Cells;Chantix;cholinergic;Cholinergic Receptors;Clinical Sciences;clinically significant;Data;Denervation;Dependence;Development;Endowment;Essential Hypertension;Evaluation;Event;Genetic;Genetic Models;Goals;Government;Health;Health system;hemodynamics;Human;human model;Hypertension;hypertensive;Immune;immune activation;Immune response;Immune system;In Vitro;in vivo;Inbred SHR Rats;Infiltration;Inflammation;Inflammatory;Kidney;kidney medulla;Knowledge;Macrophage;Maintenance;Mediating;military veteran;Modeling;Molecular;Nerve;nerve supply;Nervous System;Neuroimmune;Neuroimmunomodulation;Neurons;Neurotransmitters;Nicotine;nicotine use;Nicotinic Receptors;Norepinephrine;novel;novel therapeutics;paracrine;Pathogenesis;Pathway interactions;patient subsets;Patients;Persons;Pharmaceutical Preparations;Phenotype;Play;Population;Prevalence;Process;Production;receptor;Receptor Activation;receptor binding;Resistance;Resistant Hypertension;response;Risk;Risk Factors;Role;smoking cessation;Spleen;Testing;Therapeutic;Therapeutic Agents;varenicline;Vascular System;Veterans

PROJECT_TITLE: Inflammatory Nicotinic Acetylcholine Receptors in a Genetic Model of Essential Hypertension


ORG_CITY: NEW ORLEANS

ORG_NAME: SOUTHEAST LOUISIANA VETERANS HEALTH CARE

ORG_STATE: LA

PHR: Idiopathic pulmonary fibrosis (IPF) is a disease of aging, with limited available therapies. IPF carries a high mortality and is a disabling disease that disproportionately affects the Veterans Administration (VA) population. This project studies how aging contributes to the development and progression of IPF. Specifically, we will investigate the protective functions of sirtuins, in particular SIRT3, and the FoxO3a transcription factor in the resolution of fibrosis following lung injury in aged mice.

PI_NAMEs: THANNICKAL, VICTOR J. (contact)

PROJECT_TERMS: Accounting;Affect;Age;age related;Aging;aging mechanism;aging related disease;Alveolar Macrophages;Apoptosis;Applications Grants;Award;Binding Proteins;Bioenergetics;Bleomycin;Blood Vessels;Body System;burden of illness;Cell Aging;Cicatrix;Clinical;clinical efficacy;Complementary DNA;Cyclic AMP-Responsive DNA-Binding Protein;Data;Development;Diagnosis;disabling disease;Disease;Down-Regulation;EP300 gene;Epigenetic Process;epigenetic regulation;Event;Fibroblasts;Fibrosis;fibrotic lung;fibrotic lung disease;Gases;Genetic;Heart;histone acetyltransferase;Human;human subject;idiopathic pulmonary fibrosis;Immunohistochemistry;Impairment;improved;in vivo;Incidence;insight;Kidney;Liver;Lung;Lung Diseases;lung injury;lung repair;Macrophage;Mediating;Mitochondria;mitochondrial dysfunction;Modeling;Molecular;Morbidity - disease rate;mortality;Mus;nintedanib;novel therapeutic intervention;novel therapeutics;Nuclear;old mice;older patient;paracrine;Paracrine Communication;patient population;Pharmaceutical Preparations;pharmacologic;Phase;Phenotype;Pirfenidone;Plasmids;Population;Predisposition;Prevalence;profibrotic cytokine;protective effect;Proteins;Pulmonary Fibrosis;reconstitution;Recovery;Regulation;Resistance;Resolution;Respiratory Failure;Risk Factors;Role;senescence;Signal Pathway;Signal Transduction;Sirtuins;Structure of parenchyma of lung;Survival Rate;Testing;Time;Tissues;transcription factor;Transforming Growth Factors;United States;United States Department of Veterans Affairs

PROJECT_TITLE: Sirtuins in Lung Aging and Fibrosis


ORG_CITY: BROOKLYN

ORG_NAME: VA NEW YORK HARBOR HLTHCARE/SYS/BROOKLYN

ORG_STATE: NY

PHR: Relevance to Veterans Health: Atherosclerosis is the most common disease and contributes significantly to cardiac related morbidity and mortality in the aging population of veterans. The proposed research is intended to provide novel knowledge on distinctive function of SMSr/ PE-PLC on PE metabolism and atherosclerosis. Our findings are expected to provide novel insights in the prevention and treatment of human atherosclerosis.

PI_NAMEs: JIANG, XIAN-CHENG  (contact)

PROJECT_TERMS: aging population;Amino Acids;Animal Model;Animals;Antiatherogenic;Aorta;Apolipoproteins B;atherogenesis;Atherosclerosis;Biological Process;Cardiac;Cardiovascular Diseases;Cell Line;Cells;Ceramides;Cholesterol;Circulation;Conserved Sequence;Development;Diet;Diglycerides;Disease;Endoplasmic Reticulum;Event;Family;Fatty acid glycerol esters;feeding;Gene Family;Golgi Apparatus;Health;Hepatic;Hepatocyte;Human;Hydrolysis;Hyperlipidemia;in vivo;insight;Knowledge;Lecithin;Link;Lipids;Lipoprotein (a);Lipoproteins;Liver;Low-Density Lipoproteins;Mediating;member;Metabolism;military veteran;Morbidity - disease rate;mortality;Mus;mutant;novel;novel strategies;particle;Pathway interactions;phosphatidylcholine-specific phospholipase C;Phosphatidylethanolamine;phosphodiester;phosphoethanolamine;Phospholipids;Plasma;Play;prevent;Prevention;Process;Production;Proteins;Reaction;Recombinants;Regulation;Research;Role;Site-Directed Mutagenesis;sphingomyelin synthase;Tertiary Protein Structure;Testing;Time;Tissues;Triglycerides;Tube;Very low density lipoprotein;Veterans

PROJECT_TITLE: Effect of SMSr on VLDL metabolism and atherosclerosis


ORG_CITY: WEST HAVEN

ORG_NAME: VA CONNECTICUT HEALTHCARE SYSTEM

ORG_STATE: CT

PHR: 8. The liver is affected by several chronic diseases and these range from injury due to chronic alcohol consumption to non-alcoholic liver disease from the metabolic syndrome to viral infections, and a few genetic disorders. The feature that results in patient morbidity and mortality is the development of liver fibrosis for which there is currently no therapy  During the current Merit Review Award we have identified pyruvate kinase M2 (PKM2) as a previously unknown regulator of liver fibrosis and demonstrated that liver fibrosis can be reduced by manipulating it. In the proposed award we will fully identify how PKM2 is involved in liver fibrosis and test some novel molecules for their ability to block liver fibrosis.

PI_NAMEs: MEHAL, WAJAHAT ZAFAR (contact)

PROJECT_TERMS: Affect;Albumins;analog;Award;Binding;Biology;Cells;chronic alcohol ingestion;Chronic Disease;clinical development;Coculture Techniques;Collagen;cytokine;Data;Development;Digoxin;DNA;Drug Kinetics;EP300 gene;Event;Fibrosis;Food;Gene Expression;Genes;Genetic Diseases;Genetic Transcription;Hepatic;Hepatic Stellate Cell;Hepatocyte;HIF1A gene;High Fat Diet;Human;in vivo;in vivo evaluation;Inflammatory;inhibitor;Injury;Knock-out;Knockout Mice;Kupffer Cells;Ligands;Liver;liver development;Liver Fibrosis;Macrophage;MAPK1 gene;MAPK3 gene;Maps;Mediating;Metabolic;Metabolic syndrome;Metabolism;Mitochondrial DNA;Modeling;Morbidity - disease rate;mortality;mouse model;Mus;mutant;Mutation;National Center for Advancing Translational Sciences;new chemical entity;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;Nuclear;Nuclear Proteins;Nuclear Translocation;Oral;Pathology;Pathway interactions;Patients;Phosphorylation;Phosphorylation Site;Play;Population;Post-Translational Protein Processing;prevent;Production;Pyruvate Kinase;Reactive Oxygen Species;Regulation;Resolution;response;Response Elements;Role;Site;small molecule;small molecule inhibitor;Stimulus;Testing;Thioacetamide;Toxin;Transactivation;Transcript;Transforming Growth Factor beta;Up-Regulation;Virus Diseases;Work

PROJECT_TITLE: Regulation of Liver Fibrosis by Pyruvate Kinase M2 (PKM2)


ORG_CITY: BALTIMORE

ORG_NAME: BALTIMORE VA MEDICAL CENTER

ORG_STATE: MD

PHR: Lung cancer remains the number one cause of death in the United States, disproportionately affecting the military and Veteran population. Little information is available regarding the role of the immune system in controlling the growth of lung cancer. Here we investigate the surprising finding that CD8+ T cells, which can eliminate many types of malignancies, can accelerate the growth of lung cancer. This application focuses on understanding such mechanisms of tolerance in an effort to improve lung cancer-specific immunotherapy; and possible repurposing of existing drugs for lung cancer immunotherapy based on fundamental understanding of lung cancer biology and immunoregulation.

PI_NAMEs: KRUPNICK, ALEXANDER S. (contact)

PROJECT_TERMS: Acceleration;Adjuvant;Affect;amino acid metabolism;animal data;Animal Model;Award;base;Belief;Blood;Cancer Biology;cancer immunotherapy;Cancer Patient;Carcinogens;Cause of Death;CD8-Positive T-Lymphocytes;CD8B1 gene;Cell Line;Cells;Clinical;clinical application;Clinical Trials;Consumption;cytokine;cytotoxic;cytotoxicity;Data;Development;Disease;Down-Regulation;Environment;Failure;Gastrointestinal tract structure;Gene Silencing;General Population;Genetic Transcription;Graft Rejection;Growth;high risk;Human;Immune response;Immune system;Immune Tolerance;Immunologic Surveillance;Immunologics;immunoregulation;Immunotherapy;immunotherapy trials;improved;Interferons;Laboratories;Lewis lung carcinoma cell;Lung;Lung Transplantation;Lymphocyte;Lymphoid;MAGEA3 gene;Malignant neoplasm of lung;Malignant neoplasm of prostate;Malignant Neoplasms;Mediating;Mediator;Melanoma;Memory;Military Personnel;military veteran;Modeling;mouse model;Mucous Membrane;Mus;Natural Killer Cells;Non-Small-Cell Lung Carcinoma;novel;novel therapeutic intervention;Organ;Organ Transplantation;overexpression;Patients;Peptides;Pharmaceutical Preparations;Pharmacologic Substance;Phenotype;Play;Population;pre-clinical;programmed cell death ligand 1;Protocols documentation;rational design;response;Role;Series;Skin;Solid Neoplasm;success;synaptogenesis;T cell differentiation;T-Lymphocyte;Techniques;Testing;tissue resident memory T cell;Tissues;TNF gene;Transplantation;tumor;tumor growth;tumor microenvironment;United States;Vaccination;Veterans;Western World;Work

PROJECT_TITLE: Mechanisms of Immunosurveillance for Lung Cancer-the Role of CD8+ T Cells in Tumor Tolerance Induction


ORG_CITY: NASHVILLE

ORG_STATE: TN

PHR: PROJECT NARRATIVE Hypertension and systemic lupus erythematosus (SLE) are autoimmune conditions that are devastating and for which there are no curative therapies. Hypertension is the most common risk factor for cardiovascular disease, which is the leading cause of death amongst US veterans. SLE affects nearly 20,000 veterans and is common among minorities and women, which are growing populations amongst US veterans. This project is designed to study the function of isolevuglandins, a product of reactive oxygen species, in both conditions. These discoveries are directly applicable to the design of novel diagnostic and therapeutic approaches for cardiovascular disease and systemic autoimmunity.

PI_NAMEs: PATRICK, DAVID  (contact)

PROJECT_TERMS: adduct;Affect;Angiotensin II;Animals;Antigen Presentation;Antigen-Presenting Cells;Aortitis;Attenuated;Autoantibodies;Autoantigens;Autoimmune Diseases;autoimmune pathogenesis;autoreactive T cell;Biological Assay;blood pressure reduction;Bone Marrow;Bortezomib;Cardiovascular Diseases;cardiovascular risk factor;career;Cause of Death;Cell surface;Cells;Characteristics;Chemical Models;Chemicals;chymotrypsin;Clinical;Complex;conditional knockout;CRISPR/Cas technology;curative treatments;Data;Dendritic Cells;design;Development;Disease;disease heterogeneity;Essential Hypertension;Exhibits;experience;Experimental Models;Fatty Acids;Fellowship;Flow Cytometry;Fluorescence Resonance Energy Transfer;Human;Hypertension;hypertensive;Immune;immune activation;Immune Tolerance;Immunosuppression;Incidence;Inflammation;inhibitor;Injury to Kidney;insight;ITGAX gene;Kidney Diseases;Knowledge;Ligation;Lupus;Lysine;Mentors;MHC Class I Genes;migration;Minority;Modeling;monocyte;mouse model;multicatalytic endopeptidase complex;Mus;Mutant Strains Mice;neoantigens;novel;novel diagnostics;novel therapeutic intervention;novel therapeutics;Organ;oxidation;patient subsets;Patients;Peripheral;Peripheral Blood Mononuclear Cell;peroxidation;Plasma Cells;Population;Positioning Attribute;prevent;Pristane;Process;Production;Proteasome Inhibitor;Proteins;Publishing;Reactive Oxygen Species;recruit;Research;response;Role;systemic autoimmunity;Systemic Lupus Erythematosus;T-Cell Activation;T-Lymphocyte;Therapeutic;Tissues;Transgenic Animals;United States;Veterans;Woman

PROJECT_TITLE: A Role of Isolevuglandins in Essential Hypertension and Systemic Lupus Erythematosus


ORG_CITY: CHICAGO

ORG_NAME: JESSE BROWN VA MEDICAL CENTER

ORG_STATE: IL

PHR: Project Narrative This Collaborative Merit Award proposal (CMA) is an integrated, synergistic approach focused on the pre- invasive stage of bladder cancer (BCa), carcinoma in situ (CIS). CIS is the spreading edge of BCa, identified by abnormal, proliferating cells. The overall strategy of the CMA is to pursue mechanistic strategies to improve diagnostic and molecular therapies targeted at CIS. In CMA1, we focus on the genetic, epigenetic and expression-based pathways of proliferation, the hallmark of CIS. Our central hypothesis is that alterations of the RB1 pathway cause activation of E2F and the Enhancer of Zeste-2 (EZH2) causing cellular proliferation and immune suppression. In this proposal we will define the genetic and immunologic landscape of CIS in Veterans with smoking, and deployment related occupational chemical and biologic warfare exposure to identify new therapies for Veterans with BCa. This proposal is highly integrated with the other three proposals and will serve as a translational resource to investigate molecular mechanisms from CMAs 2-4 in Veterans with BCa.

PI_NAMEs: MEEKS, JOSHUA JAMES (contact)

PROJECT_TERMS: Address;Artificial Intelligence;artificial intelligence algorithm;Artificial Intelligence enhanced;Award;Bacillus Calmette-Guerin Therapy;base;Biological Warfare;Bladder;bladder cancer prevention;bladder carcinoma in situ;Blood;Cancer Detection;cancer initiation;cancer invasiveness;cancer risk;Carcinogens;Carcinoma in Situ;Cause of Death;Cell Cycle;Cell Proliferation;Cells;Chemical Warfare;Chemicals;Colorectal Cancer;combat;CpG Islands;Cystoscopy;Data;Detection;Diagnosis;Diagnostic;digital;DNA Methylation;Early Diagnosis;Early treatment;effective therapy;Eligibility Determination;Enhancers;Ensure;Epigenetic Process;epigenetic therapy;Epithelium;Evaluation;exhaust;exhaustion;exome sequencing;Exposure to;Foundations;Frequencies;Functional disorder;Gene Expression;Gene Mutation;Genetic;Genetic Processes;Genetic Transcription;Genomics;Goals;Hazardous Chemicals;high risk;Human;image guided;imaging biomarker;Imaging technology;Immune;immune activation;immune cell infiltrate;Immune Evasion;Immunologics;immunoregulation;Immunosuppression;Immunotherapy;improved;Indolent;Induced Mutation;inhibitor;Invaded;Invasive Lesion;KDM1A gene;Knowledge;Laboratories;Lesion;Link;Lymphocyte;Maintenance;Malignant neoplasm of lung;Malignant neoplasm of prostate;Malignant neoplasm of urinary bladder;Malignant Neoplasms;Measures;Medical center;Methods;Modeling;Molecular;molecular marker;molecular targeted therapies;Morbidity - disease rate;Muscle;Mutation;neoantigens;Neoplasm Metastasis;new therapeutic target;novel diagnostics;novel therapeutics;Occupational;Occupational Exposure;Operative Surgical Procedures;Pathologic;Pathway interactions;Patient Self-Report;Patients;personalized management;PPAR gamma;Precision therapeutics;Predictive Value;Predisposition;prevent;Prevention;Primary Care;Proliferating;promoter;RB1 gene;Reagent;Recommendation;Recording of previous events;Recurrence;Regulatory Pathway;Reporting;research and development;Resources;response;Risk;risk stratification;RNA;Role;S phase;Scientist;screening guidelines;Screening procedure;Second Primary Neoplasms;Site;small molecule inhibitor;Smoker;Smoking;Somatic Mutation;success;synergism;T-Lymphocyte;targeted sequencing;Testing;Therapeutic;therapy resistant;Time;Tobacco smoke;Tobacco smoking behavior;Transcriptional Regulation;transcriptome;treatment response;tumor;tumor progression;tumor-immune system interactions;urinary;Urine;Urologic Surgical Procedures;Urothelium;Veterans

PROJECT_TITLE: BCCMA: Basic and Translational Mechanisms of Cancer Initiation of the Urothelium in Veterans Exposed to Carcinogens: Defining the Molecular and Spatial Features of Carcinoma in situ of the Bladder


ORG_CITY: MADISON

ORG_NAME: WM S. MIDDLETON MEMORIAL VETERANS HOSP

ORG_STATE: WI

PHR: Over 29 million Americans suffer from diabetes, including 25% of Veterans seeking VA healthcare. Diabetes is defined by the failure of pancreatic β-cells to release sufficient insulin into the bloodstream to properly control blood sugar. These studies will provide new insights into the mechanisms by which β-cells depend on signals from neighboring α-cells, and explore the concept that simultaneously targeting α- and β-cells for diabetes therapy may be significantly more effective at stimulating insulin secretion than current therapies that only target β-cells. This work may lead to new therapeutic approaches to restore insulin secretion in patients with diabetes and related metabolic diseases.

PI_NAMEs: MERRINS, MATTHEW J. (contact)

PROJECT_TERMS: Adjuvant Therapy;Advanced Development;Affect;Age;Agonist;Alpha Cell;American;Amino Acids;antagonist;Anti-diabetic Drugs;Beta Cell;Biological Availability;Blood Circulation;Blood Glucose;Caring;Cell membrane;Cell Physiology;Cell secretion;cell type;Cellular Metabolic Process;Country;Cyclic AMP;Diabetes Mellitus;diabetes mellitus therapy;Dose;effectiveness testing;Electrophysiology (science);Enzymes;exenatide;Failure;Fatty Liver;Functional disorder;G-Protein-Coupled Receptors;General Population;Genetic;GLP-I receptor;Glucagon;glucagon-like peptide 1;Gluconeogenesis;Glucose;Health;Healthcare;Hormone secretion;Hormones;Human;human old age (65+);Image;imaging platform;impaired glucose tolerance;Impairment;improved;in vivo;insight;Insulin;insulin secretion;insulin sensitivity;islet;Islets of Langerhans;knock-down;Knock-out;Lipids;Liver;Membrane;Metabolic;Metabolic Diseases;Metabolism;Methods;military veteran;Mission;Mitochondria;Modeling;Molecular;Muscle;Non-Insulin-Dependent Diabetes Mellitus;novel;novel therapeutic intervention;Obese Mice;Obesity;Oral;Paracrine Communication;Patients;pharmacologic;Phase III Clinical Trials;Phosphoenolpyruvate;physiologic model;Physiological;Physiology;Plasma;Potassium Channel;pre-clinical;Pre-Clinical Model;predictive modeling;Prevalence;prevent;Prevention;Production;programs;Pyruvate;Pyruvate Kinase;pyruvate kinase deficiency;Regulation;Research;response;Role;sensor;Shapes;Signal Transduction;small molecule;sound;Structure of beta Cell of islet;Testing;Therapeutic;Three-Dimensional Imaging;United States;Veterans;Work

PROJECT_TITLE: Metabolic regulation of islet hormone secretion in diabetes


ORG_CITY: PALO ALTO

ORG_NAME: VETERANS ADMIN PALO ALTO HEALTH CARE SYS

PHR: PROJECT NARRATIVE Bladder cancer is the fourth most prevalent cancer among Veterans. Carcinoma in situ (CIS) of the bladder is a pre-invasive lesion caused by carcinogens in tobacco smoke, occupational exposures to hazardous chemicals, and chemical/biologic warfare. CIS has a high rate of recurrence and progression to invasion and metastasis. CIS is a major diagnostic challenge and up to 40% of CIS are missed by standard cystoscopy. Current approved cystoscopy technologies have significant shortcomings, particularly high false positive rates. We aim to leverage artificial intelligence to augment enhanced cystoscopy imaging technologies to improve real-time cystoscopic detection and characterization of CIS. We propose three specific aims: 1) to develop an annotated multimodal cystoscopy imaging dataset for CIS of the bladder; 2) to develop and train deep learning algorithms for detection of CIS of the bladder; and 3) to augment detection of CIS of the bladder using deep learning algorithms in clinical settings.

PI_NAMEs: LIAO, JOSEPH C (contact)

PROJECT_TERMS: Address;annotation  system;Appearance;Artificial Intelligence;artificial intelligence algorithm;Artificial Intelligence enhanced;artificial neural network;automated segmentation;Award;Bacillus Calmette-Guerin Therapy;Biological Warfare;Bladder;bladder cancer prevention;bladder carcinoma in situ;Bladder Neoplasm;Blood;Cancer Detection;cancer diagnosis;cancer initiation;cancer risk;Carcinogens;Carcinoma in Situ;Cause of Death;Characteristics;Chemicals;Clinic;Clinical;clinical application;Colorectal Cancer;Communities;Cystoscopy;Data;Data Set;deep learning algorithm;deep learning model;demographics;Detection;Diagnosis;Diagnostic;Diagnostic Sensitivity;Diagnostic Specificity;Early Diagnosis;Early treatment;Eligibility Determination;Endoscopy;Ensure;Environmental Exposure;Epigenetic Process;epigenetic therapy;Epithelium;Evaluation;Excision;experience;Exposure to;EZH2 gene;Foundations;Genetic;Genetic Transcription;Genomics;Goals;Hazardous Chemicals;Hematuria;high risk;Human;Image;Image Analysis;image guided;imaging biomarker;Imaging technology;Immune;Immunotherapy;improved;Indolent;inhibitor;Invaded;Invasive Lesion;KDM1A gene;Knowledge;Lasers;Lesion;Light;Link;Maintenance;Malignant neoplasm of lung;Malignant neoplasm of prostate;Malignant neoplasm of urinary bladder;Malignant Neoplasms;Measures;Medical center;Medical Imaging;Methods;microendoscopy;Modeling;Molecular;molecular marker;multimodality;Muscle;Neoplasm Metastasis;new therapeutic target;novel diagnostics;novel therapeutic intervention;novel therapeutics;Occupational Exposure;Operating Rooms;Operative Surgical Procedures;Optics;Papillary;Pathologic;Pathology;Patient Self-Report;Patients;personalized management;PPAR gamma;Precision therapeutics;Predictive Value;prevent;Prevention;Primary Care;Radiology Specialty;Recommendation;Recording of previous events;Recurrence;Reporting;research and development;Resolution;response;Risk;risk stratification;Role;Scientist;Screening for cancer;screening guidelines;Screening procedure;Second Primary Neoplasms;segmentation algorithm;Smoker;Smoking;Smoking History;Specificity;Staging;success;supervised learning;synergism;Technology;Testing;The Cancer Imaging Archive;Therapeutic;therapy resistant;Time;Tobacco smoke;Tobacco smoking behavior;tool;Training;Transcriptional Regulation;transfer learning;Translating;Transurethral Resection;treatment response;tumor;tumor progression;urinary;Urine;Urologic Surgical Procedures;Urologist;Urothelium;Veterans

PROJECT_TITLE: BCCMA: Basic and Translational Mechanisms of Cancer Initiation of the Urothelium in Veterans Exposed to Carcinogens: Leveraging Artificial Neural Networks to Enhance Detection of Carcinoma in situ


ADMINISTERING_IC: AI

ED_INST_TYPE: SCHOOLS OF MEDICINE

IC_NAME: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES

NIH_SPENDING_CATS: Behavioral and Social Science;Biodefense and Related Countermeasures;Clinical Research;Emerging Infectious Diseases;Health Disparities Research;Health Disparities and Racial or Ethnic Minority Health Research;Infectious Diseases;Pediatric;Rare Diseases;Social Determinants of Health;Tuberculosis

ORG_DEPT: INTERNAL MEDICINE/MEDICINE

ORG_NAME: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO

PHR: NARRATIVE There are significant gaps in our understanding of TB transmission dynamics among youth living in rural areas of East Africa. This proposal will use social and spatial network analysis to identify where, and from whom, children and adolescents acquire TB in rural Uganda. These foundational data will inform novel youth-specific interventions that are needed to expand TB control beyond the home to the community.

PI_NAMEs: MARQUEZ, CARINA  (contact)

PROGRAM_OFFICER_NAME: LACOURCIERE, KAREN A

PROJECT_TERMS: 17 year old;Address;Adolescence;Adolescent;Adult;Africa;Africa South of the Sahara;Age;age difference;age group;age related;age stratification;Age Years;Baseline Surveys;Biological Assay;burden of illness;case finding;Case/Control Studies;Characteristics;Child;cohort;Cohort Studies;Communities;Data;density;design;Disease;early childhood;Epidemic;Epidemiology;epidemiology study;HIV;Home;Hour;Household;human old age (65+);Incidence;Infection;insight;Intervention;Interview;Investigation;Knowledge;Life Cycle Stages;Location;Longitudinal cohort study;Measurement;Measures;Methodology;Methods;Molecular Epidemiology;Network-based;novel;novel strategies;Outcome;Pathway Analysis;Persons;Population;population based;preference;Prevalence;prospective;Research Infrastructure;Role;Rural;rural area;Rural Community;scale up;School-Age Population;secondary analysis;sex;social;Social Network;Socialization;Source;Structure;Surveys;Techniques;Television;Testing;therapy design;Time;transmission process;Tuberculin Test;Tuberculosis;Uganda;Variant;Work;young adult;Youth

PROJECT_TITLE: Socio-spatial Networks and Tuberculosis Infection in Youth in Rural Uganda

STUDY_SECTION_NAME: Special Emphasis Panel[ZRG1-PSE-N(90)]


ORG_CITY: MATHER

ORG_NAME: VA NORTHERN CALIFORNIA HEALTH CARE SYS

PHR: My research interest focuses on molecular mechanisms on hormone regulation and function in the pathogenesis of neurodegenerative and cardiovascular disease, two major health burdens for our Veterans. We seek to determine the fundamental molecular signals of insulin and adrenergic hormones that regulate cellular function and understand the dysregulation of molecular pathways that contributes to disease development in animal models. The overall goal is to identify novel molecular targets and strategies for prevention and intervention of diseases. Specifically, our current VA merit review award is to delineate the mechanisms underlying the novel signaling induced by cardiac beta1-adrenergic receptor in development of heart failure. These investigations will provide novel molecular insights to facilitate further studies and to translate into therapeutic strategies for patient care, thus improving the Veterans' health and reduce health care cost.

PI_NAMEs: XIANG, YANG K (contact)

PROJECT_TERMS: ADRBK1 gene;Adrenergic Agents;Adrenergic Receptor;alpha synuclein;Alzheimer's Disease;Amyloid beta-Protein;Angiotensins;Animal Model;Asthma;Atrial Fibrillation;Award;beta-2 Adrenergic Receptors;beta-adrenergic receptor;biochemical tools;Biosensor;Brain;California;Cardiac;Cardiac Myocytes;Cardiac Output;Cardiovascular Diseases;Cardiovascular Physiology;Cardiovascular system;career;Cell Physiology;Chronic;Chronic Disease;Chronic Obstructive Pulmonary Disease;Circulation;Clinical;clinical practice;Clinical Trials;Cognition;cognitive function;Collaborations;comorbidity;Complex;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;Cyclic GMP;cytokine;Data;Depressed mood;desensitization;Development;Diabetes Mellitus;diabetic;diabetic patient;Disease;DLG1 gene;Drug Screening;EFRAC;Emotions;Epinephrine;Fibrosis;flexibility;Functional disorder;Funding;Genes;Genetic;Genomics;Goals;Grant;GRK5 gene;Health;Health Care Costs;Heart Diseases;Heart failure;heart function;Homeostasis;hormone regulation;Hormones;Human;Hyperglycemia;Hyperinsulinism;Impairment;improved;Inflammation;Inflammatory;inhibitor;insight;Insulin;Insulin Receptor;insulin signaling;interest;Interleukin-1 beta;Intervention;Investigation;Joints;Laboratories;Learning;life span;Link;live cell imaging;Membrane Proteins;Memory;Memory Loss;Mentors;Metabolic;Metabolic Diseases;Metabolic syndrome;Metabolism;military veteran;Molecular;Molecular Target;Muscle Cells;Nature;Nerve;Neurodegenerative Disorders;Neurohormones;Neurons;neurotoxicity;new therapeutic target;Nitric Oxide;novel;novel strategies;novel therapeutic intervention;Outcome;Pain;Parkinson Disease;Pathogenesis;Pathologic;Pathway interactions;Patient Care;Patients;Pharmaceutical Preparations;Physicians;Prevention strategy;Privatization;programs;Prostaglandins;protein complex;Proteins;Proteomics;Protocols documentation;Quality of life;receptor;Receptor Signaling;Regulation;Research;Research Personnel;response;Role;Science;Scientist;Services;Signal Induction;Signal Pathway;Signal Transduction;Signaling Molecule;single molecule;spatiotemporal;Stress;Synapses;System;Therapeutic;Therapeutic Intervention;Tissues;Transgenic Model;Translating;United States National Institutes of Health;Veterans


ORG_CITY: AUGUSTA

ORG_NAME: CHARLIE NORWOOD VA MEDICAL CENTER

PHR: PROJECT NARRATIVE The proposed research is relevant to veterans’ health because, understanding the mechanism by which spermine oxidase (SMOX) causes neuronal damage and dysfunction in Multiple Sclerosis (MS), will facilitate the development of novel therapeutic strategies for preventing vision loss in MS patients. Our studies will impact field of MS research by providing new and significant information on mechanisms to preserve optic nerve integrity and visual function. Our findings will be relevant to the mission of the VA and will be broadly interesting to researchers studying molecular mechanisms of neurodegenerative diseases.

PI_NAMEs: NARAYANAN, PRIYA  (contact)

PROJECT_TERMS: Acrolein;adduct;Affect;Aldehydes;Antioxidants;Axon;Behavioral;behavioral outcome;Blindness;Blood-Retinal Barrier;Brain;Clinical;clinically significant;Cognitive;Contrast Sensitivity;Defect;Demyelinations;Dependovirus;Development;Disabling;disabling disease;Disease;Disease Progression;Down-Regulation;Enzymes;Experimental Autoimmune Encephalomyelitis;Experimental Models;Eye;Functional disorder;genetic approach;Gliosis;Goals;Health;improved;Induced Neurons;Inflammation;Inflammatory;Inflammatory Response;inhibitor;insight;Long term disability;Measures;Mediating;Mediator;Metabolic Pathway;Mission;mitochondrial dysfunction;Modeling;Modification;Molecular;Morphology;Motor;motor deficit;motor impairment;Multiple Sclerosis;multiple sclerosis patient;multiple sclerosis treatment;Mus;Nerve Degeneration;Nervous System Disorder;Neurodegenerative Disorders;neuroinflammation;Neuronal Dysfunction;neuronal survival;Neurons;New Agents;new therapeutic target;novel;novel therapeutic intervention;Onset of illness;Optic Nerve;Optic Neuritis;Outcome;overexpression;oxidation;oxidative damage;Oxidative Stress;Parkinson Disease;Pathology;Pharmaceutical Preparations;pharmacologic;Phase;Play;polyamine oxidase;Polyamines;pre-clinical;preservation;prevent;progressive neurodegeneration;Proteins;Quality of life;Research;Research Personnel;response;Retina;Retinal Ganglion Cells;retinal nerve fiber layer;retinal neuron;Role;Sampling;short hairpin RNA delivery;Spinal cord injury;Structure;Symptoms;targeted agent;targeted treatment;Testing;theories;Therapeutic;therapeutic target;Thinness;tool;Transgenic Mice;translational approach;Traumatic Brain Injury;treatment effect;Unmyelinated Nerve Fibers;Up-Regulation;Veterans;Vision;Visual Acuity;visual dysfunction;Visual impairment;Visual Pathways

PROJECT_TITLE: Targeting spermine oxidase to prevent vision loss in Multiple Sclerosis


ORG_CITY: BRONX

ORG_NAME: JAMES J PETERS VA  MEDICAL CENTER

PHR: Amyotrophic lateral sclerosis (ALS) is a deadly neurodegenerative disease with higher incidence in U.S. Veterans and is considered to be a service-connected condition. Understanding the biological basis of ALS remains a major challenge. Whereas the original focus of ALS research was concentrated on the degenerating motor neurons, distinct yet overlapping pathology in different cells types have been reported in ALS patients. The proposed research will use state-of–the-art approaches to study ALS in different brain cell types from the autopsied brains of U.S. Veterans.

PI_NAMEs: DRACHEVA, STELLA  (contact)

PROJECT_TERMS: Accounting;Address;Affect;Aliquot;ALS pathology;ALS patients;Amyotrophic Lateral Sclerosis;Anatomy;Astrocytes;Autopsy;biobank;Biological;Brain;brain cell;brain tissue;C9ALS;C9ORF72;cell cortex;Cell Nucleus;cell type;Cells;Central Nervous System;Cessation of life;Classification;Communities;Data;Disease;Endothelial Cells;Environmental Exposure;Etiology;excitatory neuron;excitotoxicity;Fluorescence;Frontotemporal Dementia;frontotemporal lobar dementia amyotrophic lateral sclerosis;Gene Expression;Gene Expression Profiling;General Population;Genes;Genetic Predisposition to Disease;Genetic Transcription;genome-wide analysis;Glutamates;Human;illness length;Incidence;Individual;insight;Large-Scale Sequencing;Link;Masks;Microglia;military veteran;Molecular;molecular pathology;Motor;Motor Cortex;motor neuron degeneration;Motor Neurons;Mutation;Names;Neurodegenerative Disorders;Neuroglia;neuron loss;Neurons;neurotoxic;novel;Nuclear;Oligodendroglia;Pathology;Pathway interactions;Patients;Phenotype;Play;Prefrontal Cortex;Preparation;Proteins;Protocols documentation;Reporting;Research;Resolution;Rest;Role;Sampling;Services;Severities;Signal Transduction;single nucleus RNA-sequencing;Sister;Sorting;Specimen;Symptoms;Testing;transcriptome;transcriptome sequencing;Translating;United States Department of Veterans Affairs;Veterans

PROJECT_TITLE: Cell-type-specific molecular pathology of ALS in U.S. military Veterans


ORG_CITY: ANN ARBOR

ORG_STATE: MI

PHR: NARRATIVE Brain vascular disease causes and augments dementia in a very large number of Veterans, but the molecular origins of vascular pathology are unclear. We have discovered a sequence of new events in brain blood vessels in the inherited cerebrovascular disease CADASIL. We aim to study the significance of one of the last steps in this sequence, a conformational change in a fragment of NOTCH3.

PI_NAMEs: WANG, MICHAEL M (contact)

PROJECT_TERMS: Acceleration;Address;Affect;age related;Age related pathologies;Alzheimer's Disease;Alzheimer's disease related dementia;Amino Acids;amyloid pathology;Antibodies;Arterial Disorder;Arteries;Atherosclerosis;Automobile Driving;autosome;Binding;Blood Vessels;Brain;Brain Diseases;Brain Pathology;Cause of Death;cerebral artery;Cerebrovascular Disorders;Cerebrovascular system;Cerebrum;Classification;Clinical;Collaborations;CTSH gene;Cysteine;demented;Dementia;Deposition;Deterioration;disability;Disease;Disease Marker;Disease Progression;effective therapy;EGF gene;Elderly;Event;Exhibits;experimental study;Functional disorder;Generations;Impairment;Inherited;Investigation;Leptomeninges;Lifelong disability;Magnetic Resonance Imaging;military veteran;Modeling;Molecular;Molecular Conformation;Monoclonal Antibodies;Mutation;N-terminal;Names;Neurodegenerative Disorders;NOTCH3 gene;novel;nuclear transport factor 2;Parkinson Disease;Pathologic;Pathology;Penetration;Peptides;Play;premature;Process;Protein Conformation;Proteins;Role;Severities;Severity of illness;Stroke;Structure;Subcortical Infarctions;Subcortical Leukoencephalopathy;Surface;Testing;vascular cognitive impairment and dementia;Vascular Dementia;Vascular Diseases;Veterans;white matter;Work

PROJECT_TITLE: Advanced conformational changes in NOTCH3 and cerebrovascular disease severity


ORG_CITY: BIRMINGHAM

ORG_NAME: BIRMINGHAM VA MEDICAL CENTER

ORG_STATE: AL

PHR: Project Narrative My major research focus is to understand the fundamental mechanisms of gene regulation and function in the development of cardiovascular disease, a major health burden for our veterans. Our overarching goals are to translate the findings into identification of novel molecular targets and strategies for prevention and intervention of cardiovascular disease. With the ongoing collaboration with physician scientists and basic scientists at the Birmingham VA medical center and UAB, our ongoing investigations will not only elucidate the precise molecular and cellular mechanisms governing vascular smooth muscle cell reprograming in the pathogenesis of vascular disease and aging; but also provide novel molecular insights facilitating further studies to translate these findings into therapeutic strategies for patient care, so as to improve the veterans’ health, life span and quality of life, and reduce health care costs.

PI_NAMEs: CHEN, YABING  (contact)

PROJECT_TERMS: Aging;Alabama;Animal Model;Atherosclerosis;Award;Blood Vessels;bone;calcification;Cardiovascular Diseases;cardiovascular health;career;Cell Physiology;Cell Reprogramming;Cells;Circadian Dysregulation;circadian pacemaker;Collaborations;Development;Diabetes Mellitus;diabetic;Funding;Gene Expression Regulation;gene function;General Population;Goals;graduate student;Grant;Health;Health Care Costs;Hyperglycemia;improved;innovation;insight;Intervention;Investigation;knockout gene;Knockout Mice;life span;Macrophage;Medical center;Mentors;Military Personnel;Mission;Molecular;Molecular Target;mouse model;new therapeutic target;next generation;novel;osteogenic;Oxidative Stress;Pathogenesis;Patient Care;Phenotype;Physicians;Postdoctoral Fellow;Prevention strategy;programs;Quality of life;Regulation;Research;Research Personnel;Research Project Grants;Role;Scientist;Services;Smooth Muscle Myocytes;stem cells;Therapeutic;Tissues;Training;transcription factor;Translating;United States National Institutes of Health;Universities;Up-Regulation;Vascular calcification;Vascular Diseases;Vascular Smooth Muscle;Veterans

PROJECT_TITLE: BLRD Research Career Scientist Award Renewal


ORG_CITY: BUFFALO

ORG_NAME: VA WESTERN NEW YORK HEALTHCARE SYSTEM

PHR: Eye injuries leading to compromised or lost vision are among the signature injuries sustained by our Veterans and deployed soldiers engaged in the recent conflicts in Iraq and Afghanistan (OEF, OIF). Currently, about 170,000 Veterans are legally blind, and nearly 1.5 million have some kind of visual deficit that is battle-related. Traumatic brain injury (TBI) is another signature injury of those conflicts; a significant percentage of TBI patients suffer visual deficits, nearly a third of which are blast-induced. Our goal is to understand the molecular and cellular mechanisms underlying such vision loss, and to find practical pharmacological interventions to prevent or retard the progression of those visual deficits. In addition, we’re investigating a form of Retinitis Pigmentosa (RP), about which very little is known, initially in an effort to understand the causes of the associated retinal degeneration at the molecular level and eventually to develop gene therapy approaches to ameliorate or prevent that degeneration and vision loss.

PI_NAMEs: FLIESLER, STEVEN J. (contact)

PROJECT_TERMS: 7-dehydrocholesterol reductase;Ablation;academic standard;Acoustics;Affect;Afghanistan;Antioxidants;Award;Biochemistry;Biological;Biomedical Research;blast exposure;Blindness;Book Chapters;Brain;career;career development;Caring;Categories;cell type;Cellular biology;Cerebral cortex;Cholesterol;Cholesterol Homeostasis;Clinical;clinical translation;Collaborations;Communities;Congenital disorders of glycosylation;cytotoxic;Defect;Deficiency Diseases;Development;Devices;Diphosphates;Disease;distinguished professor;Dolichol;Educational process of instructing;Endowment;Enzymes;Equilibrium;Eukaryotic Cell;evidence base;Exhibits;Explosion;Exposure to;Extramural Activities;Eye;Eye Injuries;Faculty;falls;fighting;Foundations;Functional disorder;Funding;gene therapy;Genes;Genetic Diseases;Glial Fibrillary Acidic Protein;Gliosis;glycosylation;Goals;graduate student;Grant;Grant Review;Human;Human Genetics;improved;Inherited;Injury;insight;Institution;International;International Aspects;Intervention;Investigation;Iraq;isoprenoid;Journals;Lateral;lectures;Legal Blindness;legally blind;Liquid substance;medical schools;Medical Students;member;Mentors;Mission;Modeling;Molecular;mouse model;Mutation;Nonpenetrating Wounds;novel;Ocular Pathology;Ophthalmology;Participant;peer;Peer Review;Penetration;Percussion;Persons;pharmacologic;Photoreceptors;Postdoctoral Fellow;Predisposition;preservation;pressure;prevent;Privatization;Productivity;Professional Organizations;programs;Proteins;Publications;Publishing;Rattus;Recording of previous events;Regulation;Reporting;Research;Research Personnel;Retina;Retinal Degeneration;Retinitis Pigmentosa;Role;Safety;Science;Scientist;senior faculty;Services;Shock;Site;Smith-Lemli-Opitz Syndrome;Soldier;Source;Sterols;Structure;symposium;System;TBI Patients;Testing;therapeutic evaluation;Therapeutic Intervention;therapeutically effective;Trauma;Traumatic Brain Injury;Traumatic injury;Tube;undergraduate student;United States National Institutes of Health;Universities;Up-Regulation;Veterans;Vision;Vision Disorders;Vision research;Visual;Visual Acuity;visual dysfunction;Visual Fields;Visual System;War

PROJECT_TITLE: BLRD Research Career Scientist Award Application


PHR: Project Narrative  An effective vaccine is requisite for controlling HIV infections in at-risk individuals. These include Veterans cared for in the Veterans Affairs health care system. Preventing HIV infection will save the VA countless millions of dollars otherwise needed for life-long care of HIV-infected Veterans. The proposed study will produce our lead vaccine under cGMP and optimize its delivery with the ensuing goal of a phase I vaccine trial in humans. Our vaccine is unique in that it is designed to elicit a focused antibody response against a specific site on the virus; antibodies against this domain of the virus Env protein have been shown to reduce virus infection. The strongest support for the efficacy of this approach comes from the RV144 clinical vaccine trial, the only human vaccine trial demonstrating partial but significant efficacy against HIV infection. The novel vaccine to be developed in the studies described in this application was designed to improve upon the RV144 vaccine.

PI_NAMEs: HIOE, CATARINA E (contact)

PROJECT_TERMS: 2019-nCoV;Adherence;AIDS prevention;Anti-Retroviral Agents;Antibodies;Antibody Formation;Antibody Response;antibody-dependent cell cytotoxicity;antibody-dependent cellular phagocytosis;Antigens;Biomanufacturing;Caring;Cells;Clinical Trials;Collaborations;Complement Activation;COVID-19;cross reactivity;Data;design;Development;Disease;DNA;economic impact;efficacy clinical trial;env Gene Products;Epitopes;Escherichia coli;Future;Glycoproteins;glycosylation;Goals;Good Manufacturing Process;Healthcare Systems;HIV;HIV envelope protein;HIV Envelope Protein gp120;HIV Infections;HIV vaccine;Home;Human;Immune;Immune response;Immunization;Immunize;Immunodominant Epitopes;immunogenic;immunogenicity;Immunoglobulin G;improved;In Vitro;in vivo;Individual;Infection;Laboratories;Lead;Legal patent;Macaca mulatta;Mediating;Medical center;medical schools;Methods;Monkeys;Monoclonal Antibodies;monomer;nonhuman primate;novel;novel vaccines;Oryctolagus cuniculus;Outcome;pandemic disease;pathogen;Pathway interactions;Phase;Phase I Clinical Trials;Plasma;plasmid DNA;Plasmids;prevent;Production;Protein Analysis;protein purification;Proteins;prototype;Provider;Publishing;rational design;Recombinants;Regimen;Research;Risk;RNA Splicing;scaffold;Scaffolding Protein;simian human immunodeficiency virus;Site;SIV;standard of care;Supervision;Testing;Transfection;United States Department of Veterans Affairs;United States Dept. of Health and Human Services;Universities;Vaccination;vaccine candidate;Vaccine Clinical Trial;vaccine efficacy;vaccine strategy;vaccine trial;vaccine-induced antibodies;Vaccines;Vagina;Validation;Veterans;Veterans Health Administration;Viral Physiology;Virion;Virus;Virus Diseases;virus envelope;Wisconsin

PROJECT_TITLE: Vaccine targeting HIV sites of vulnerability


ORG_CITY: OKLAHOMA CITY

ORG_NAME: OKLAHOMA CITY VA MEDICAL CENTER

PHR: The public health crisis known as “the opioid epidemic” continues to take the lives of veterans, not only due to the development of opioid use disorders and overdose but also from an enhanced risk of suicide. Improved treatments for opioid use disorders are desperately needed, but the neurophysiological adaptations that drive increased reinforcement in these individuals are not adequately understood. The proposed studies will combine electrophysiological, behavioral, molecular, and cell type-specific techniques in mice to elucidate the relationship between the modulatory peptide neurotensin, inhibitory synaptic transmission, and opioid self- administration. The mechanistic understanding gleaned from this work will help identify novel therapeutic targets to treat opioid use disorders in veterans and the general population.

PI_NAMEs: BECKSTEAD, MICHAEL J (contact)

PROJECT_TERMS: Ablation;Abstinence;adverse outcome;Affect;Affinity Chromatography;Aging;aldehyde dehydrogenase 1;Alleles;analog;Area;Astrocytes;Attention;Behavior;Behavioral;Bioinformatics;Brain;Breeding;Cell Nucleus;cell type;Chest;chronic pain management;Clinical;Code;Cre lox recombination system;Cues;Data;Dependovirus;designer receptors exclusively activated by designer drugs;Development;Disease;Disinhibition;DNA;dopamine transporter;dopaminergic neuron;drug reinforcement;Electrophysiology (science);Enterobacteria phage P1 Cre recombinase;epigenomics;experience;experimental study;Family member;Female;Fentanyl;gamma-Aminobutyric Acid;Gene Expression;gene interaction;Gene Modified;General Population;Genes;Genetic;Glean;Hypothalamic structure;improved;Individual;Injections;innovation;Intake;Knock-out;Knowledge;Label;Lateral;Link;LoxP-flanked allele;Maintenance;male;Measures;Mediating;Molecular;mouse genetics;mu opioid receptors;Mus;neuronal excitability;Neurons;neurophysiology;Neurotensin;Neurotensin Receptors;Neurotransmitters;new therapeutic target;Nociception;novel;Nuclear;Nucleic Acids;Nucleus Accumbens;Opioid;opioid abuse;opioid epidemic;opioid exposure;Opioid Receptor;opioid use;opioid use disorder;optogenetics;Overdose;Pain;Pain management;patch clamp;Pathway interactions;Peptides;Pharmaceutical Preparations;Physiological;prescription opioid;presynaptic;Procedures;Property;Psychological reinforcement;Public Health;Quality of life;Rattus;receptor;Receptor Signaling;Recording of previous events;Relapse;remifentanil;Ribosomes;Risk;RNA;Role;Self Administration;side effect;Signal Transduction;Site;Slice;Source;suicidal risk;Suicide;Synapses;Synaptic plasticity;Synaptic Transmission;System;Techniques;Testing;Titrations;tool;transcriptome;transcriptomics;Translating;treatment strategy;Ventral Tegmental Area;vesicular GABA transporter;Veterans;Viral;Virus;Withdrawal;Work;Writing

PROJECT_TITLE: Plasticity of GABA input to VTA dopamine neurons in opioid use disorders


PHR: The VA patient population is increasingly suffering from osteoporosis due to low bone mineral density (BMD). Current estimates indicate that 12 million people suffer from osteoporosis in the U.S., largely influenced by genetics. This project seeks to identify the gene and mechanism responsible for a locus influencing bone mineral density. Successful completion of this project will have the potential to lead to new therapies for the treatment of osteoporosis.

PI_NAMEs: CLEMENS, THOMAS L (contact)

PROJECT_TERMS: 14q32;Affect;Affinity;Area;Base Pairing;Bioenergetics;Biological;Biological Assay;Biology;bone;Bone Density;bone mass;Capital;career;causal variant;Cell division;Chromosome Mapping;Chromosomes;Collaborations;Complex;CRISPR/Cas technology;Data;Dissection;Elements;Femur;follow-up;fracture risk;Genes;Genetic;Genetic Determinism;Genetic Variation;genome wide association study;genome-wide;genomic locus;Genomics;global health;Heritability;Human;In Vitro;Intervention;Introns;knock-down;Knowledge;Link;Luciferases;male;men;Methodological Studies;Microtubules;mineralization;Mus;Mutation;Neck;Network-based;Neuronal Differentiation;notch protein;novel;novel therapeutics;Osteoblasts;Osteoporosis;osteoporosis with pathological fracture;Pathology;Pathway interactions;patient population;Persons;Phenotype;Phosphotransferases;Predisposition;Prevalence;Process;programs;Protein-Serine-Threonine Kinases;Regulator Genes;Regulatory Pathway;Reporter;Research;Risk;RNA Splicing;Role;Scientist;Serine;Signal Transduction;skeletal;Skeleton;social;synergism;Testing;Thick;trait;Universities;Variant;Veterans;Veterans Health Administration;Virginia

PROJECT_TITLE: Functional Dissection of the MARK3 GWAS Locus for Bone Mineral Density


PHR: NARRATIVE The human gut microbiota contributes to obesity, insulin resistance, and the subsequent development of type 2 diabetes (T2D). The primary role of the gut microbiome is to digest fiber, which results in short chain fatty acids (SCFAs). The body has a means to sense to SCFAs, via the receptors, FFA2 and FFA3. Here, we propose to investigate how SCFAs from fiber are sensed by the body, and also explore their individual roles in key tissues, in pancreatic β cells and enteroendocrine L cells. And finally, through translational studies, we will explore the applicability of these receptors to human physiology. In sum, this proposal will result in novel insight into FFA2 and FFA3 in the body, and its therapeutic value.

PI_NAMEs: LAYDEN, BRIAN THOMAS (contact)

PROJECT_TERMS: Acceleration;Acetates;Affect;Agonist;antagonist;B-Lymphocytes;Beta Cell;Biological Assay;Blood;body sense;Butyrates;Cell Physiology;Cell secretion;cell type;Cells;Data;detection of nutrient;Development;Diabetes Mellitus;Diet;dietary;Dietary Fiber;Dietary Intervention;Disease;Drug Targeting;Event;Fermentation;FFAR2 gene;Fiber;Genetic;glucagon-like peptide 1;gut bacteria;gut microbiome;gut microbiota;Health;Hormone secretion;Human;human disease;human tissue;In Vitro;Individual;insight;Insulin Resistance;insulin secretion;Intake;Intervention;Intestines;islet;Knock-out;Knockout Mice;L Cells;Measures;Mediating;Medical;meetings;Metabolic;Metabolic Diseases;Metabolism;military veteran;Modeling;Morbidity - disease rate;mortality;mouse model;Mus;Non-Insulin-Dependent Diabetes Mellitus;Nonesterified Fatty Acids;novel;Obesity;obesogenic;Outcome;Output;Pathway interactions;Peptide YY;Pharmaceutical Preparations;pharmacologic;Pharmacology;Physiology;Production;Propionates;receptor;receptor function;Receptor Signaling;response;Role;Signal Transduction;Site;Societies;Structure;Structure of beta Cell of islet;Supplementation;Testing;Therapeutic;therapeutic target;Tissues;Translating;translational potential;translational study;Veterans;Volatile Fatty Acids;western diet

PROJECT_TITLE: Role of Nutrient Sensing Receptors for the Gut Microbiota in Metabolism


ORG_CITY: PITTSBURGH

ORG_NAME: VETERANS HEALTH ADMINISTRATION

ORG_STATE: PA

PHR: More than 1.5 million veterans have diabetes and this is associated with a significant increase in complications and death. All diabetes is associated with an inability to compensate by increasing the number and function of the insulin producing β-cells in the pancreas to meet the metabolic needs. The precise molecular mechanisms regulating β-cell compensation are poorly understood. With compelling preliminary data that Tead1 regulates β-cell proliferation and function in mice, we propose to identify molecular mechanisms underlying the regulation of β-cell proliferation, differentiation and acquisition of mature function by Tead1 in human β-cells, using human iPS cell-derived β-cells, to translate the findings from mouse studies to diabetes therapy in humans. Successful completion of the proposed experiments will help close the knowledge gap in our understanding of the regulation of proliferation and differentiation in human β-cells and will help develop novel therapies that preserve and restore β-cells to cure diabetes.

PI_NAMEs: YECHOOR, VIJAY K (contact)

PROJECT_TERMS: Address;Adult;age related decline;Aging;American;Apoptosis;Beta Cell;beta cell replacement;Cell Differentiation process;Cell Maintenance;Cell Maturation;Cell Physiology;Cell Proliferation;cell replacement therapy;cell type;Cells;Cessation of life;cofactor;Compensation;Data;Diabetes Mellitus;diabetes mellitus therapy;diabetes risk;druggable target;Embryo;Endocrine;Enhancers;experimental study;Failure;functional decline;Functional disorder;gain of function;General Population;Genes;Genetic;Genetic Transcription;Glucose;Glucose Intolerance;Goals;High Fat Diet;Human;human induced pluripotent stem cells;Impairment;improved;in vivo;Incidence;induced pluripotent stem cell;Insulin;Insulin Resistance;insulin secretion;islet;islet stem cells;Knowledge;loss of function;Mediating;Metabolic;Metabolic stress;military veteran;Molecular;Molecular Target;Morbidity - disease rate;mortality;mouse model;Mus;mutant;Non-Insulin-Dependent Diabetes Mellitus;novel;novel therapeutics;Nuclear;Nuclear Translocation;Obesity;overexpression;Pancreas;Pathway interactions;Phenotype;Phosphorylation;Phosphotransferases;Predisposition;preservation;prevent;Process;progenitor;Proliferating;Regulation;Reporting;response;Rest;Role;stress state;System;Testing;transcription factor;Transcriptional Activation;Transcriptional Regulation;Translating;translational therapeutics;Veterans

PROJECT_TITLE: Novel Regulators of Beta Cell Proliferation and Function


ORG_CITY: Decatur

PHR: There are over 30,000 HIV-infected veterans in the VA and about 2000 at the Atlanta VA. Despite combined antiretroviral therapy (cART), approximately half of these individuals develop HIV associated neurocognitive disorders (HAND). Our screening of 41 consecutive HIV-infected veterans at the Atlanta VA indicates that 43% have HAND, which is consistent with most published data and suggests a substantial number with HAND within VHA. Fortunately, most of these veterans with HAND have mild memory impairments. However, eventually these mild deficits become severe, leading to dementia and death, even if they receive cART. So, it is vitally important to develop specific treatments for HAND and that is the purpose of the studies that are proposed. We plan to develop an animal model that will allow us to test potential treatments for HAND. If they work in the animal model they can be tested in humans with HAND.

PI_NAMEs: TYOR, WILLIAM R (contact)

PROJECT_TERMS: Aging;aging population;Alzheimer's Disease;Animal Model;Animals;antiretroviral therapy;arm;Basal Ganglia;Behavior;Biological;BLT mice;Brain;cell type;Cells;Cessation of life;Clinical;Clinical Trials;Cognitive deficits;cognitive testing;comorbidity;Data;Dementia;Development;disease model;DNA;efficacy testing;Exhibits;Flow Cytometry;frontal lobe;Future;glial activation;Hippocampus;HIV;HIV Infections;HIV-associated neurocognitive disorder;Human;humanized mouse;Individual;Infection;Infiltration;Inflammatory;inhibitor;Legal patent;Long-Term Effects;Memory impairment;Methods;Modeling;Monitor;Mononuclear;mouse model;Mus;Neurons;novel;object recognition;Pathologic;Pathology;Patients;Persons;Phagocytes;predictive modeling;Publishing;Radial;Reaction;Rheumatoid Arthritis;Risk;RNA;Safety;SCID Mice;screening;Stroke;T-Lymphocyte;Techniques;Testing;Time;trafficking;treatment effect;treatment strategy;Validation;Veterans;Water;Work

PROJECT_TITLE: Validating a Humanized Mouse HIV Model for Cognitive Deficits and Novel Treatments


ORG_CITY: Aurora

ORG_NAME: VA EASTERN COLORADO HEALTH CARE SYSTEM

ORG_STATE: CO

PHR: Virus-induced diseases of the central nervous system (CNS) cause significant morbidity and mortality throughout the world. West Nile virus (WNV) is the leading cause of epidemic encephalitis in the US and probably the most common cause of all viral encephalitis during summer months in virus-targeted regions. The veteran population is highly enriched for those at most risk of WNV-induced neuroinvasive disease (90% male, 56% over age 60). This grant will determine the role of microglia in WNV-induced CNS pathogenesis and will evaluate microglia as potential therapeutic targets for WNV-induced CNS disease. Microglia are also critically important to many neurodegenerative and acquired CNS diseases (ALS, Parkinson's, Alzheimer's, traumatic brain and spinal cord injury) which have a major impact on veterans' health. In summary, this is a basic science grant, with translational components, that assesses the importance of microglia in WNV-induced CNS disease. Our findings will have direct relevance to a wide variety of neurological diseases affecting veterans.

PI_NAMEs: TYLER, KENNETH L. (contact)

PROJECT_TERMS: Address;Affect;Age;Alzheimer's Disease;antagonist;Antigen-Presenting Cells;antigen-specific T cells;Arbovirus Encephalitis;Astrocytes;Basic Science;Bone Marrow Transplantation;Brain;cell injury;Cells;Central Nervous System;Central Nervous System Diseases;Central Nervous System Infections;central nervous system injury;Cessation of life;chemokine;Clinical;Cognitive;comparison control;cytokine;Data;Disease;efficacy evaluation;Elderly;Excision;experimental study;FDA approved;Grant;Granulocyte-Macrophage Colony-Stimulating Factor;Growth;Health;Hematopoietic Cell Growth Factors;Human;Immune;Immune system;improved;in vivo;Infection;Inflammatory;Injury;Invaded;leukemia;Macrophage Colony-Stimulating Factor Receptor;male;Microglia;military veteran;Modeling;Monitor;Morbidity - disease rate;mortality;Mus;Nerve Degeneration;Nervous System Disorder;Nervous System Trauma;Neurocognitive;Neurodegenerative Disorders;neuroinflammation;Neurologic;Neurons;neurotoxic;novel therapeutic intervention;Parkinson Disease;pathogen;Pathogenesis;Pathogenicity;Pathology;Peripheral Nervous System;Phagocytosis;Phagocytosis Inhibition;Play;Population;Probability;Proliferating;Recombinants;Recovery;release factor;response;Risk;Role;sargramostim;Severities;Slice;Spinal Cord;spinal cord and brain injury;T cell response;T-Lymphocyte;Testing;therapeutic target;therapeutically effective;Time;tissue injury;Tissues;Transplant Recipients;treatment strategy;United States;Veterans;Viral;Viral Encephalitis;Virus;Virus Diseases;Virus Replication;West Nile viral infection;West Nile virus;White Blood Cell Count procedure

PROJECT_TITLE: Role of Microglia in Protection Against West Nile Virus-induced CNS Injury: mechanisms and treatment strategies


PHR: Mild traumatic brain injuries (mTBIs) resulting from explosive blasts are common in military personnel and can result in epilepsy and sensory dysfunction. Veterans with mTBI and a family history of epilepsy are significantly more likely to have post-mTBI seizures. We will investigate mechanisms by which mTBI and genetics interact to produce seizures, somatosensory dysfunction and thalamocortical network reorganization and we will determine if a therapeutically analogous form of neurostimulation targeted to a specific sensory network reduces symptoms.

PI_NAMEs: GALLAGHER, MARTIN J (contact)

PROJECT_TERMS: Afghanistan;Anatomy;Animal Model;Awareness;Brain;Brain Injuries;Brain region;Cellular biology;Classification;Clinical;clinical translation;combat;comorbidity;Data;density;Development;Disease;Electric Stimulation;Electroencephalography;epidemiology study;Epilepsy;experience;experimental study;Family history of;First Degree Relative;Focal Seizure;Foundations;Functional disorder;Future;Gene Expression;Generalized seizures;Genetic;Genetic Predisposition to Disease;Genetic Risk;genetic risk factor;Headache;Hemorrhage;Heterozygote;Histology;Human;Human Resources;Implant;Individual;Injury;innovation;Investigation;Iraq;Lead;Long-Term Effects;Measures;Methods;mild traumatic brain injury;Military Personnel;minimally invasive;Modernization;Monitor;mouse model;Mus;neurobehavioral test;Neurologic Dysfunctions;Neurons;neurophysiology;novel;Pain;Patients;Physiology;Play;Predisposition;reduce symptoms;Risk;risk variant;Role;Seizures;Sensory;Services;somatosensory;Somatosensory Cortex;TBI Patients;TBI treatment;Testing;Therapeutic;Traumatic Brain Injury;Veterans;Wild Type Mouse

PROJECT_TITLE: Interactions of traumatic brain injury with pre-existing mild epilepsy on thalamocortical dysfunction, sensory processing, and seizures


ORG_CITY: NORTHPORT

ORG_NAME: NORTHPORT VA MEDICAL CENTER

PHR: Thrombotic microangiopathy is the most severe form of renal endothelial cell injury and occurs subsequent to a wide variety of diseases. Untreated, ongoing renal microvascular injury uniformly progresses to chronic kidney disease and end stage renal disease, of which both have increased prevalence amongst the Veteran population. The proposed project, uncovering the mechanisms of transcriptional regulation behind renal endothelial cell injury and its sensitivity to complement activation is a critical step in identifying novel targets for therapy as well as providing new insights into renal microvascular pathobiology.

PI_NAMEs: ESTRADA, CHELSEA  (contact)

PROJECT_TERMS: Acceleration;Advisory Committees;Age;Albuminuria;Anti-Inflammatory Agents;antibody-mediated rejection;Applications Grants;Attenuated;Basic Science;Binding;Binding Sites;Biopsy;Biopsy Specimen;Blood Vessels;cadherin 5;career development;CD46 Antigen;CD55 Antigens;cell injury;chromatin immunoprecipitation;Chronic Kidney Failure;Clinical Research;clinical training;Complement;Complement Activation;Complement Membrane Attack Complex;Cre lox recombination system;Data;Development Plans;differential expression;Disease;End stage renal failure;Endothelial Cells;Endothelium;Etiology;Exhibits;experience;experimental study;Foundations;Funding;Gene Chips;Genes;genetic regulatory protein;Genetic Transcription;GKLF protein;Glomerular Capillary;glomerular endothelium;Goals;Growth Factor Inhibition;Hemolytic-Uremic Syndrome;Histologic;Histology;Homeostasis;Human;human RNA sequencing;in silico;Inflammation;Inflammatory;inhibitor;Injury;insight;KDR gene;Kidney;kidney biopsy;Kidney Diseases;Kidney Transplantation;knock-down;Laboratories;Luciferases;Maintenance;Malignant Hypertension;Measures;Mediating;Mediator;Medical center;Medicine;Membrane;Mentors;Mentorship;military veteran;Modeling;Molecular;mouse model;Mus;Nephrology;new therapeutic target;Nitric Oxide Synthase;NOS3 gene;novel;overexpression;Pathology;Pathway interactions;pharmacologic;Phenotype;Physicians;Plasminogen Activator Inhibitor 1;Postdoctoral Fellow;Predisposition;Prevalence;prevent;Productivity;promoter;Promoter Regions;Publications;Regulation;Renal glomerular disease;Reporter;Research;Research Personnel;Research Training;response to injury;Role;Scientist;Shiga Toxin;Shiga-Like Toxin II;small molecule;Specimen;success;Swelling;Testing;thrombotic;Thrombus;Transcript;transcription factor;Transcriptional Regulation;transcriptome sequencing;Translational Research;Transplantation;United States Department of Veterans Affairs;vascular bed;Vascular Cell Adhesion Molecule-1;Vascular Endothelial Cell;Vascular Endothelial Growth Factors;Vascular Endothelium;vascular injury;von Willebrand Factor;Wild Type Mouse;Zinc Fingers

PROJECT_TITLE: Transcriptional Regulation of Thrombotic Microangiopathy in the Renal Microvasculature


PHR: The proposed project will take an integrated genomic approach to understand how the risk and clinical severity of idiopathic pulmonary fibrosis (IPF) is modified by the molecular machinery that regulates gene expression. The end-result will be an enhanced understanding of the novel genes, regulatory pathways and networks, and molecular mechanisms involved in the etiology and clinical severity of IPF. Given the demographics of IPF, veterans represent an at-risk population for IPF who will benefit significantly from an improved understanding of the pathogenesis of pulmonary fibrosis.

PI_NAMEs: SCHWARTZ, DAVID ALBERT (contact)

PROJECT_TERMS: Affect;Biological;Biological Assay;Biology;Clinical;clinical heterogeneity;Code;Complex;Data;demographics;Development;differential expression;Disease;DNA;DNA Methylation;Epigenetic Process;Etiology;Fibroblasts;gain of function;Gene Expression;Gene Expression Profile;Genes;Genetic;Genetic Determinism;Genetic Diseases;Genetic Predisposition to Disease;Genetic Risk;genetic risk factor;Genetic Transcription;genetic variant;genome-wide;Genomic approach;Goals;idiopathic pulmonary fibrosis;improved;Individual;insight;Length;Link;Lung;Messenger RNA;MicroRNAs;Molecular;molecular diagnostics;molecular phenotype;Molecular Profiling;molecular subtypes;MUC5B gene;novel;Pathogenesis;Pathologic;Pathway interactions;Patients;Penetrance;Peripheral Blood Mononuclear Cell;Phenotype;Populations at Risk;Prognosis;Proliferating;promoter;Proteins;Pulmonary Fibrosis;Quantitative Trait Loci;Rare Diseases;Regulation;Regulatory Pathway;Reporter;Research;Resources;Risk;Risk Factors;risk variant;RNA;RNA analysis;Role;Sampling;Severities;Signal Transduction;Structure of parenchyma of lung;telomere;Testing;transcription factor USF;transcriptome;transcriptome sequencing;transcriptomics;Untranslated RNA;Variant;Veterans

PROJECT_TITLE: lncRNAs, Linking Genetic Susceptibility to Molecular Phenotype in IPF


ORG_CITY: COLUMBIA

ORG_NAME: HARRY S. TRUMAN MEMORIAL VA HOSPITAL

ORG_STATE: MO

PHR: Healthy arteries stretch with each heart beat to receive blood pumped from the heart, then constrict to propel blood forward to target organs. With normal aging and in response to several diseases, arteries stiffen, which plays a key role in major cardiovascular diseases, including hypertension, heart failure, and stroke. Arteries contain smooth muscle cells (SMCs), which constrict and relax to regulate blood flow. It recently became recognized that SMCs themselves stiffen with aging. In addition, SMCs, like other cells throughout the body, become senescent, which leaves them unable to divide and makes them secrete proteins that promote inflammation. This proposal will examine how plasminogen activator inhibitor-1 (PAI-1), a protein that controls blood clotting and several cell functions, promotes stiffening and senescence of SMCs and arteries. The effects of drug inhibition of PAI-1 will also be examined, which we anticipate will lead to new approaches to prevent vascular stiffening and its serious adverse effects.

PI_NAMEs: FAY, WILLIAM P (contact)

PROJECT_TERMS: Actins;Adverse effects;Affect;Age;Aging;Alteplase;arterial stiffness;Arteries;Atherosclerosis;Atomic Force Microscopy;Biology;Blood;Blood coagulation;Blood flow;blood pressure regulation;blood pump;Blood Vessels;burden of illness;candidate identification;Cardiac;Cardiovascular Diseases;Cardiovascular Physiology;Cardiovascular system;Cell Adhesion;Cell Aging;Cell division;cell motility;Cell Physiology;Cells;Clinical;Clinical Trials;clinically relevant;cofilin;conditional knockout;constriction;Cytoskeleton;dalton;Data;Disease;Drug Targeting;experience;experimental study;F-Actin;fatty acid oxidation;Fibrosis;fitness;Fluorescence Microscopy;Focal Adhesions;Generations;Genetic;Glycolysis;Goals;Heart;Heart failure;Hospitals;Hypertension;in vivo;Inflammation;inhibitor;innovation;LDL-Receptor Related Protein 1;Link;Measurement;Mediating;medical schools;member;Membrane Potentials;military veteran;Missouri;Mitochondria;mitochondrial membrane;mouse model;multidisciplinary;Mus;Myocardial Infarction;Myosin ATPase;normal aging;novel;novel strategies;Organ;Oxygen Consumption;Pathologic;Pathway interactions;Peripheral arterial disease;Pharmaceutical Preparations;pharmacologic;Phenotype;Plasminogen Activator Inhibitor 1;Play;prevent;Production;Protease Inhibitor;Protein Secretion;Proteins;Proteolysis;Reactive Oxygen Species;recruit;Relaxation;Research;respiratory;response;Role;Scientist;senescence;senescence associated secretory phenotype;Serpin Superfamily;Signal Pathway;Smooth Muscle Myocytes;Stress Fibers;Stretching;Stroke;Testing;transcriptome sequencing;Translating;Trees;Universities;Urokinase;Vascular Diseases;vascular inflammation;Vascular Smooth Muscle;Veterans;Work

PROJECT_TITLE: Role of Plasminogen Activator Inhibitor-1 in Vascular Smooth Muscle Cell Stiffening and Senescence


PHR: Available treatments for chronic obstructive pulmonary disease (COPD), a very common and progressive fatal disease that afflicts many among the high proportion of VA patients who are smokers, provide no more than short-term benefits, if any. Nur77 is an orphan receptor in cell nuclei, whose incompletely known functions include anti-inflammatory actions and the ability to induce cell death by apoptosis in certain circumstances. The receptor is unusual in that it can be activated by ligand binding to either of two distinct sites. Based on our novel identification of the first known ligand for Nur77’s binding site 2 and finding that it stimulates Nur77’s anti- inflammatory activity more effectively than classic site 1 ligands while uniquely blocking Nur77-involved apoptosis, this project will determine the role of Nur77 in COPD and test the mechanisms and potential therapeutic value of novel Nur77 activation site 2 activators. Our anticipated finding will thus point toward a new avenue of effective COPD therapy.

PI_NAMEs: REDDY, RAJU C (contact)

PROJECT_TERMS: Address;Adverse effects;Age;Agonist;airway epithelium;airway inflammation;airway obstruction;airway remodeling;alveolar destruction;Anti-Inflammatory Agents;Apoptosis;Apoptotic;Binding;Binding Sites;Biological Assay;Cause of Death;Cell Death Induction;Cell Nucleus;Chronic;Chronic Obstructive Pulmonary Disease;cigarette smoke;cigarette smoke-induced;cigarette smoke-induced COPD;cigarette smoke-induced inflammation;cigarette smoke-induced lung injury;cigarette smoking;Computer Simulation;Covalent Interaction;Cytoplasm;Data;Disease;disease model;Disease Progression;DNA Binding;Down-Regulation;drug candidate;Epithelial Cells;Exhibits;exposed human population;exposure to cigarette smoke;Functional disorder;Genes;Genetic Transcription;Human;improved;in silico;In Vitro;in vivo;Inflammation;Inflammatory;Inflammatory Response;Inhalation;innovation;insight;Intervention;knock-down;Knock-out;Ligand Binding;Ligands;Lung;lung injury;Mediating;Methods;military veteran;Mitochondria;Modeling;Molecular Conformation;mouse model;Movement;Mus;New Agents;new therapeutic target;novel;novel therapeutics;Nuclear;Nuclear Export;Nuclear Hormone Receptors;Nuclear Localization Signal;Nuclear Orphan Receptor;Orphan;Oxidative Stress;Pathogenesis;Pathogenicity;Pathway interactions;Patients;Peptide Hydrolases;pre-clinical;Prevalence;promoter;Pulmonary Emphysema;pulmonary function;Pulmonary Inflammation;receptor;Receptor Activation;Research;response;Response Elements;Role;RXR;screening;Severities;Severity of illness;Signal Transduction;Site;Smoker;Smoking;smoking cessation;Structure of parenchyma of lung;Testing;Therapeutic;therapeutic target;tool;toxicant;Toxicology;Transgenic Mice;treatment effect;treatment response;Up-Regulation

PROJECT_TITLE: Nur77: Novel Mechanistic Insights and Activation in COPD


ORG_STATE: GA

PHR: Project Narrative: The goal of this project is to validate a new, innovative treatment for neuropathic pain after spinal cord injury (SCI-NP) using a novel and highly clinically-relevant pig model. We will validate exciting findings from research in rodents which discovered a highly efficacious treatment for SCI-induced neuropathic pain in a large animal model with characteristics similar to human SCI. The new therapy is to deliver a gene construct encoding 6 copies of the NMDA antagonist serine-histrogranin and one copy of the opioid agonist endomorphin 1 (6SHG/EM1) via intraspinal delivery as reported in Jergova et al., 2017. We hypothesize that administration of 6SHG/EM1 after SCI will significantly reduce neuropathic pain. We will use quantitative sensory testing methods used in human medicine to evaluate neuropathic pain in pigs. The results of this study are a critical next step in translation of this new therapy to clinical trials, and ultimately to provide relief to Veterans who suffer from pain.

PI_NAMEs: FLOYD, CANDACE L. (contact)

PROJECT_TERMS: Acceleration;adeno-associated viral vector;adenovirus mediated delivery;Affect;Affective;allodynia;Anatomy;Animal Model;Animals;antagonist;Back;Biological Assay;Blood;Caring;Cells;Cerebrospinal Fluid;Characteristics;Chest;chronic neuropathic pain;chronic pain;Clinical;Clinical Trials;clinically relevant;collaborative approach;Collection;Contusions;Data;delivery vehicle;Dependovirus;dermatome;Development;Disease;Documentation;dorsal horn;Dose;efficacious treatment;endomorphin 1;Euthanasia;Evaluation;experience;experimental study;Family suidae;first-in-human;Gene Delivery;gene therapy;Genes;Goals;good laboratory practice;Human;Hypersensitivity;Immune response;Immunosorbents;Impairment;Injections;Injury;innovation;Intrathecal Injections;Investigational New Drug Application;Laboratory Research;Life;Link;Location;Medical;Medicine;Methodology;Methods;Modeling;Motor;N-Methylaspartate;Naloxone;Neurons;neutralizing antibody;novel;novel therapeutics;Opioid agonist;Pain;pain outcome;Pain Research;pain scale;painful neuropathy;Pathology;Patients;Pattern;Peptides;Persons;Physiology;porcine model;Positioning Attribute;pressure;Prevalence;Rattus;Reporting;Research;response;Rodent;scale up;Sensory;Serine;Seroprevalences;Spinal;Spinal Cord;Spinal cord injury;Spinal Cord Lesions;Spinal Ganglia;Spinal Injections;Stimulus;Tactile;Testing;Therapeutic;Time;Tissues;Transfection;transgene expression;Transgenes;Translating;translational goal;Translations;United States Food and Drug Administration;Validation;vector;Veterans;Veterans Health Administration

PROJECT_TITLE: Evaluation of 6SHG/EM1 as a treatment for spinal cord injury-induced neuropathic pain in a pig model


ORG_CITY: RICHMOND

ORG_NAME: VA VETERANS ADMINISTRATION HOSPITAL

ORG_STATE: VA

PHR: Narrative Infections with the bacterium Pseudomonas aeruginosa are a significant problem among our veterans, and they are difficult to treat due to its innate antibiotic resistance. Many VAMC patients are susceptible to opportunistic infections with P. aeruginosa due to complications with COPD, emphysema, chronic bronchitis and during treatment with respiratory ventilators. A key virulence factor of P. aeruginosa during pulmonary infection is the production of a capsule-like exopolysaccharide called alginate. A better understanding of the complex mechanisms involved in alginate biosynthesis and gene expression could lead to novel therapies. This work also includes the search for novel therapeutics to treat Pseudomonas pulmonary infections.

PI_NAMEs: OHMAN, DENNIS EDWARD;ZHOU, HUIPING ROSE (contact)

PROJECT_TERMS: Acetylation;Acute Pneumonia;Affect;Agar;Alginates;Anabolism;anti-microbial drug;Antibiotic Resistance;Antibiotics;Antineoplastic Agents;Award;Bacteremia;Bacteria;Bacteria sigma factor KatF protein;Cancer Patient;capsule;Catheters;Cells;Chemicals;chemotherapy;Chronic;Chronic Bronchitis;Chronic Obstructive Pulmonary Disease;Clinical;Complex;Complication;Cystic Fibrosis;derepression;Development;Disease;Effectiveness;Environment;Enzymes;Exposure to;Gene Expression;gene product;Genetic Transcription;Goals;Immune response;Immunosuppressive Agents;improved;in vivo;Infection;Knowledge;Life;Liquid substance;Lung;Lung Diseases;Lung infections;Membrane;Microbial Biofilms;Modification;Molecular;Morbidity - disease rate;Morphology;mortality;mucoid;mutant;Mutation;Nosocomial Infections;novel therapeutic intervention;novel therapeutics;Occupational;Operative Surgical Procedures;Operon;Opportunistic Infections;opportunistic pathogen;Pathogenesis;pathogenic bacteria;Pathogenicity;Pathway interactions;Patients;Phagocytes;Phagocytosis;Pharmaceutical Preparations;Pharmacotherapy;Phenotype;Phosphorylation;Play;Pneumonia;polymerization;Polymers;Polysaccharides;Positioning Attribute;Predisposition;pressure;Process;Production;Pseudomonas;Pseudomonas aeruginosa;Pseudomonas aeruginosa infection;Pulmonary Emphysema;Regulation;Research;Resistance;respiratory;Respiratory Tract Infections;Role;Sigma Factor;Signal Transduction;small molecule libraries;Small RNA;Spinal Puncture;Stimulus;Stress;Therapeutic;Therapeutic Agents;Therapeutic Uses;Thick;Toxin;transcriptome;transcriptome sequencing;Untranslated RNA;Ventilator;Veterans;Virulence Factors;Work

PROJECT_TITLE: Pathogenic Mechanism for Lung Infection in Mucoid Pseudomonas


PHR: Tauopathies are a group of diseases in which accumulation of a brain protein called `Tau' damages brain cells. These diseases, which include Alzheimer's dementia and head injury, are collectively a major cause of chronic disability in veterans. There are currently no effective treatments for tauopathies; medications that prevent disease progression would have a significant and positive impact on veterans' health. To address this challenge, we identified chemicals that prevent deterioration of brain function in a novel animal model of tauopathy. One of these chemicals blocks a type of brain inflammation that is thought to mediate the progression of symptoms in tauopathy. In this project, we will define the precise cellular and molecular mechanisms by which this chemical prevents neurological problems the tauopathy model, and test whether this approach could be exploited to develop an anti-tauopathy medication.

PI_NAMEs: BURTON, EDWARD ALAN (contact)

PROJECT_TERMS: Acetylation;Address;Affinity;Alzheimer's Disease;Animal Model;Autopsy;Binding;Biochemical;Biological Models;Brain;brain cell;Brain Injuries;brain tissue;Bromodomain;cancer clinical trial;Cells;Chemicals;Chronic;Chronic disability;chronic traumatic encephalopathy;clinical development;Clinical Trials;comparative efficacy;Complement;Craniocerebral Trauma;CRISPR/Cas technology;Cytoplasm;Data;density;Deterioration;Development;Disease;Disease Progression;effective therapy;Encephalitis;Event;Exposure to;Flow Cytometry;Frontotemporal Dementia;Funding;Gene Expression Profile;Gene Expression Profiling;Genetic;Genetic Transcription;glial activation;Gliosis;Glutathione;Health;Human;hyperphosphorylated tau;in vivo;Infiltration;Inflammatory;inhibitor;innovation;intravital imaging;Length;Link;Lysine;Measures;Mediating;Microglia;microscopic imaging;migration;Modeling;Molecular;Morphology;Motor;mutant;Natural Immunity;Nerve Degeneration;Nervous System Physiology;Neurodegenerative Disorders;neuroinflammation;Neurologic;Neurologic Deficit;Neurologic Dysfunctions;Neurological disability;neuron loss;Neurons;new therapeutic target;novel;novel strategies;oculomotor;oxidation;Oxidative Stress;Pathogenesis;Pathogenicity;Pathologic;Pathway interactions;Patients;Pharmaceutical Preparations;Phenotype;Phosphorylation;Play;prevent;Process;programs;Progressive Supranuclear Palsy;Proteins;ratiometric;Recovery;Reporter;response;Role;selective expression;Shapes;Signal Transduction;Small Molecule Chemical Library;Symptoms;Synapses;synaptic pruning;tau aggregation;tau expression;tau Proteins;Tauopathies;Testing;Therapeutic;therapeutic target;Toxic effect;Transgenic Mice;Transgenic Organisms;translational potential;Veterans;Work;Zebrafish

PROJECT_TITLE: Role of BET proteins in neuroinflammation in tauopathy