ORG_CITY: BOSTON

PHR: Amyotrophic lateral sclerosis (ALS) is an incurable fatal neurologic disease leading to progressive paralysis and, in many cases, cognitive decline. There is no effective treatment for ALS and its ultimate cause remains unknown. Because studies suggest that veterans are at increased risk for ALS, VA established ALS as a 100% service-connected disability. VA has made a major commitment to support research on ALS and funded the creation of the VA Biorepository Brain Bank (VABBB) as a national resource to support ALS research. Enrolled veterans with ALS across the country receive semi-annual telephone calls to collect health information. Upon a veteran’s death, the VABBB arranges for the collection of brain and spinal cord tissue for processing, storage, and distribution to qualified ALS investigators. The availability of high-quality tissue and clinical data from veterans enrolled in the VABBB is an essential resource to support research on the causes and effects of ALS and the development of effective treatments for those affected by this devastating disease.

PI_NAMEs: MCKEE, ANN C. (contact);ZHU, HAINING

PROJECT_TERMS: Acceleration;Adult;Affect;Age;Amyotrophic Lateral Sclerosis;amyotrophic lateral sclerosis therapy;Arizona;Autopsy;Behavior assessment;Behavioral;biobank;Biological;Blood;bone;Boston;Brain;Central Nervous System;Cessation of life;chronic traumatic encephalopathy;Clinical;clinical care;Clinical Data;Cognitive;cohort;Collaborations;Collection;Communication;Consensus;Country;Data;Data Collection;data management;Databases;Development;Diagnosis;Diagnostic;diagnostic criteria;disability;Disease;Disease Progression;disorder control;effective therapy;Enrollment;Environmental Risk Factor;Etiology;Evaluation;Family member;Financial cost;follow-up;frontotemporal lobar dementia amyotrophic lateral sclerosis;Functional disorder;Funding;Generations;Genetic;genetic linkage;Genetic Markers;genome sequencing;Genomics;Health;health administration;Healthcare Systems;Human;Huntington Disease;Impaired cognition;improved;Incidence;International;Investments;Link;Low Prevalence;male;Medical Informatics;Medical Records;meetings;military service;military veteran;Modeling;mouse model;Muscle;National Institute on Aging;Nature;Nervous System Disorder;Neurodegenerative Disorders;neuropathology;non-genetic;novel;operation;Paralysed;Pathology;Persons;Prevalence;Process;Progress Reports;Prospective, cohort study;Proteomics;Qualifying;Recommendation;recruit;Research;Research Personnel;Research Support;Resources;Risk;Risk Factors;RNA;Sampling;Scientific Advances and Accomplishments;Services;sex;Sex Factors;Site;societal costs;Spinal Cord;targeted treatment;Telephone;Time;Tissue Banks;tissue processing;Tissue Sample;Tissues;United States Department of Veterans Affairs;Veterans;Veterans Health Administration;whole genome

PROJECT_TITLE: VA Biorepository Brain Bank


ADMINISTERING_IC: VA

ARRA_FUNDED: N

FUNDING_MECHANISM: NON-SBIR/STTR RPGS

IC_NAME: Veterans Affairs

ORG_CITY: CHICAGO

ORG_COUNTRY: UNITED STATES

ORG_FIPS: US

ORG_NAME: JESSE BROWN VA MEDICAL CENTER

ORG_STATE: IL

PHR: Emerging evidence supports the critical role of gut microbiome in development of Veterans’ deployment related GI and liver diseases. To date, however, the role of Gulf War Illness (GWI) microbiome in diarrheal diseases in GWI has not been investigated. The proposed studies in this application, based on our exciting preliminary data from a humanized GWI mouse model established by us are aimed at investigating the mechanisms underlying the higher incidence of diarrheal diseases in GWI veterans. We propose to utilize both the humanized mice (fecal microbial transplant or FMT from GWI veterans), and conventional GWI mice (war chemical induced) to understand the causative role of GWI microbiome in increasing susceptibility to diarrheal pathogens and the mechanisms involved. We will also assess the therapeutic role of FMT from healthy donors, probiotics and bacterial metabolite butyrate in GWI. The studies may unravel new targets for better treatment of GWI Veterans utilizing novel approaches to alter microbiome.

PI_NAMEs: DUDEJA, PRADEEP K (contact)

PROJECT_TERMS: absorption;Address;Animal Model;Apical;Award;beneficial microorganism;Bicarbonates;Biological Response Modifier Therapy;Butyrates;Chemicals;Chlorides;Chronic stress;Citrobacter rodentium;Clostridium difficile;Collaborations;Colon;Data;Development;Diarrhea;diarrheal disease;Disease;dysbiosis;E-Cadherin;efficacy evaluation;Electrolytes;enteropathogenic Escherichia coli;Event;Exhibits;Exposure to;fecal transplantation;Fluids and Secretions;Functional disorder;Funding;Gastroenterology;Gastrointestinal Diseases;Gulf War;gut dysbiosis;gut inflammation;gut microbiome;healthcare burden;Human;human subject;humanized mouse;imaging system;in vivo Model;in vivo optical imaging;Incidence;Infection;Inflammation;Inflammatory Bowel Diseases;Intestinal Absorption;intestinal barrier;Intestines;Ions;Journals;Knockout Mice;Knowledge;Link;Liver diseases;meetings;Metagenomics;Microbe;microbial;microbiome;microbiome alteration;Modality;Modeling;Morbidity - disease rate;mouse model;Mus;Neutrophil Infiltration;novel;novel strategies;novel therapeutics;occludin;Outcome;overexpression;pathogen;Pathogenesis;Persian Gulf Syndrome;Phenotype;Play;Post-Traumatic Stress Disorders;Predisposition;Probiotics;Proteins;Publishing;Research;Research Personnel;Risk;Role;SLC26A3 gene;sodium-hydrogen exchanger 3;Source;Structure;Symptoms;Technology;Therapeutic;Time;transcriptome sequencing;Transgenic Mice;translational impact;treatment strategy;Veterans;War

PROJECT_TITLE: BCCMA: Targeting Gut-Microbiome in Veterans Deployment Related Gastrointestinal and Liver Diseases; CMA1- The Role of GWI Gut Microbiome in Susceptibility to Diarrheal Diseases


FUNDING_MECHANISM: OTHERS

ORG_CITY: HOUSTON

ORG_NAME: MICHAEL E DEBAKEY VA MEDICAL CENTER

ORG_STATE: TX

PHR: Hospital admissions are challenging for adults with dementia and for the family and friends who care for them. Following hospital discharge, adults with dementia often have increased care needs, which places new demands on their family and friends. Family and friends are critical to ensuring that Veterans with dementia can live safely in the community following discharge. Healthcare systems have an opportunity to support family and friends of adults with dementia by addressing dementia specific caregiving challenges that arise during the transition from hospital to home. However, there are no support interventions for dementia caregivers that have been developed or tested as part of hospital care. In this proposal, we will design and test a novel support intervention for the family and friends who care for hospitalized Veterans with dementia. This proposal aligns with the research priorities of the Veterans Health Administration and the National Institute on Aging to identify strategies to support the family and friends who provide care to adults with dementia across care settings.

PI_NAMEs: HORSTMAN, MOLLY JANE (contact)

PROJECT_TERMS: acceptability and feasibility;Acute;acute care;acute stress;Address;Adult;Adverse event;Agreement;Alzheimer's disease caregiver;Alzheimer's disease related dementia;Ambulatory Care;Anxiety;Area;arm;Award;care giving burden;care recipients;career development;Caregiver Burden;caregiver depression;caregiver stress;Caregiver support;Caregivers;caregiving;Caring;Chronic;Cognitive;Communities;Community Healthcare;Data;Delirium;Dementia;dementia care;Dementia caregivers;dementia caregiving;design;Development;E-learning;Education;efficacy testing;Emotional;Ensure;Event;evidence base;Evidence based intervention;experience;falls;Family;Family Caregiver;family support;Friends;Future;Geriatrics;Goals;Health;Health education;Health Services;Health Status;Healthcare Systems;Home;hospital care;hospital readmission;Hospitalists;Hospitalization;Hospitals;human centered design;implementation science;improved;improved outcome;Inpatients;Intervention;Interview;Learning;loved ones;Measures;Medical center;Medicine;Mental Depression;Mentors;Mollies;mortality;multi-component intervention;multidisciplinary;National Institute on Aging;novel;older adult;online delivery;Online Systems;Outcome;Outcome Measure;Patient-Focused Outcomes;Patients;Personal Satisfaction;Physicians;primary outcome;Problem behavior;programs;Randomized;Randomized, Controlled Trials;recruit;Reporting;Research;Research Methodology;Research Personnel;Research Priority;Resources;retention rate;Risk;Role;Sample Size;Schedule;Scientist;Self Care;Sentinel;Site;skills training;Social support;Specialist;Stroke;Structure;System;Testing;Therapeutic;therapy design;Training;Translating;Veterans;Veterans Health Administration;web-based intervention

PROJECT_TITLE: Hospital GamePlan4Care: A Web-Based Delivery System for Dementia Caregiver Support


ORG_CITY: NORTH LITTLE ROCK

ORG_NAME: CENTRAL ARKANSAS VETERANS HLTHCARE SYS

ORG_STATE: AR

PHR: Prostate cancer (PCa) is a major health issue among military veterans in the United States. Metal exposures experienced during deployment and post-deployment likely have significant impacts on PCa risk in veterans. Inorganic arsenic (iAs) and lead (Pb) are classified as a carcinogen and potential carcinogen, respectively, in humans. Demographic data on veterans and their occupations suggest a potential risk for veterans to be exposed to metals, such as iAs and Pb, in environmental and occupational settings. However, the underlying molecular mechanisms that link metal exposure and PCa are understudied. This application will test the hypothesis that iAs or Pb transforms prostate epithelial stem-like cells to initiate or increase PCa risk in a mouse model. Our research using a novel approach of single-cell RNA-seq will reveal this rare epithelial stem cell population in the adult prostate as the possible origin of metal-associated prostate cancer and provide novel specific biomarkers that will advance our current strategies for assessing PCa risk and treating the disease in humans.

PI_NAMEs: HO, SHUK-MEI  (contact)

PROJECT_TERMS: Accounting;Address;Adsorption;Adult;Afghanistan;Agar;age group;androgen independent prostate cancer;Androgen Suppression;Animal Model;Animals;Anniversary;anti-cancer research;Aromatic Polycyclic Hydrocarbons;Arsenic;Award;Barker Hypothesis;Biological Markers;bisphenol A;Body Fluids;burn pit;Canada;cancer diagnosis;Cancer Patient;Cancer Research Project;cancer stem cell;carcinogenesis;carcinogenicity;Carcinogens;career;Cell Death;Cell Separation;Cells;Censuses;chemical carcinogen;Chemicals;Childhood Asthma;Chronic Disease;Classification;Clinical Research;Communities;comparison control;Congresses;consumer behavior;Data;data registry;Databases;Department of Defense;Dermal;Development;Diagnostic;disability;Disease;disorder risk;Disparity;Drug Targeting;early life exposure;Educational workshop;Endocrine disruption;Endocrine Disruptors;Environment;Environmental and Occupational Exposure;Environmental Exposure;Environmental Health;environmental toxicology;Epidemiology;Epigenetic Process;epigenomics;epithelial stem cell;Epithelium;ESR1 gene;Estrogen Receptor 2;Estrogens;European Union;experience;Exposure to;Funding;General Population;Genes;genetic signature;Genetic Transcription;Goals;Gonadal Steroid Hormones;GPER gene;Grant;hazard;Health;high risk;High-Risk Cancer;Hormonal Carcinogenesis;hormone regulation;Human;immunodeficiency;improved;in vivo;Incidence;indexing;Influentials;Informatics;Ingestion;Inhalation;insight;International;International Agencies;Intervention;Ions;Iraq;Joints;Kidney Transplantation;Knowledge;late life;Lead;lead exposure;Lead levels;Lesion;Life;Link;male;Malignant neoplasm of prostate;Malignant Neoplasms;Mediating;Medical Research;member;Metal Carcinogenesis;Metal exposure;Metals;metaplastic cell transformation;Methylation;Military Personnel;military service;military veteran;Molecular;mouse model;Mus;National Institute of Diabetes and Digestive and Kidney Diseases;National Institute of Environmental Health Sciences;National Toxicology Program;neoplasm registry;novel;novel strategies;Occupational;Occupational Exposure;Occupations;Ohio;Oils;Oncogenic;Paper;Participant;Peer Review;Policies;Population;precision medicine;premalignant;prevent;Productivity;programs;promoter;Prostate;prostate cancer cell;prostate cancer model;prostate cancer prevention;prostate cancer risk;prostate carcinogenesis;Prostatic Epithelium;Protein Isoforms;public health intervention;public health research;Publishing;Refuse Disposal;Reporting;Research;Risk;Risk Factors;Role;Safety;Scientist;Seminal;Signal Pathway;single-cell RNA sequencing;Smoke;Societies;Source;specific biomarkers;stem cell biology;stem cell population;stem cells;stem-like cell;Strategic Planning;symposium;Testing;The Cancer Genome Atlas;Therapeutic;toxicant;Toxicant exposure;Toxicology;transcriptomics;Translating;Translations;trend;Tumor Suppressor Proteins;Umbilical Cord Blood;understudied cancer;United States;United States Department of Veterans Affairs;United States National Institutes of Health;urinary;Urine;urologic;Urology;Veterans;Visualization;Woman;Work

PROJECT_TITLE: BLRD Research Career Scientist Award Application


PHR: PROJECT NARRATIVE This Collaborative Merit Award application (CMA) is a synergistic, multidisciplinary project focused on the mechanistic understanding of platinum resistance (PtR) as the foremost cause of death in ovarian cancer patients. The overall strategy is to integrate ideas, resources, and expertise in advanced technologies to identify and validate novel therapeutic targets and biomarker-driven treatments for ovarian cancer patients. This application (CMA2) will study metabolic reprograming associated with emergence of PtR focusing on a shift from glycolysis to fatty acid oxidation in PtR HGSOC cells and tumors. The project will use novel single cell metabolic imaging (stimulated Raman scattering) along with lipidomic measurements to define metabolic vulnerabilities of resistant HGSOC. The deliverables of CMA2 will be a molecular imaging based prognostic test to recognize PtR and new enzymatic inhibitors as novel therapeutic approaches for PtR HGSOC.

PI_NAMEs: MATEI, DANIELA E (contact)

PROJECT_TERMS: Address;Award;Biological Assay;Biological Markers;biomarker driven;Breast Cancer Cell;cancer cell;Cancer Patient;cancer recurrence;cancer stem cell;Carbon;Cause of Death;Cell Death;Cell Death Induction;Cell Line;Cells;Cellular biology;Cessation of life;Chemicals;Chemoresistance;chemotherapy;Clinical;clinical development;Clinical Management;clinically relevant;Collaborations;Collecting Cell;Colorectal Cancer;Consumption;Data;Dependence;desaturase;Development;digital;Disease Progression;Disease remission;Disease Resistance;DNA Damage;DNA Repair Pathway;Energy-Generating Resources;Enzymes;Fatal Outcome;fatty acid oxidation;Fatty Acids;Fatty-acid synthase;Fluorescence;Generations;Genetic;Glucose;Glutamine;Glutathione;Glycolysis;Goals;Human;Image;Imaging Device;imaging modality;Imaging Techniques;Immunocompetent;Immunotherapy;indexing;Induction of Apoptosis;inhibitor;kinase inhibitor;lipid biosynthesis;Lipid Peroxidation;lipidomics;Lipids;Malignant Epithelial Cell;Malignant neoplasm of lung;Malignant neoplasm of ovary;Malignant Neoplasms;Measurement;Measures;Mediating;Membrane Lipids;Membrane Transport Proteins;Metabolic;metabolic abnormality assessment;metabolic imaging;Metabolism;Methods;Modeling;Molecular;Molecular and Cellular Biology;molecular imaging;Monitor;mouse model;multidisciplinary;multimodality;Multiomic Data;Mus;neoplastic cell;new therapeutic target;novel;novel strategies;novel therapeutic intervention;Organoids;Ovarian;ovarian neoplasm;Ovarian Serous Adenocarcinoma;oxaliplatin;Oxidative Stress;oxidized lipid;Pathway interactions;patient derived xenograft model;Patients;Peroxides;Phenotype;Platinum;pre-clinical;Pre-Clinical Model;Predisposition;prevent;Process;prognostic assays;Reactive Oxygen Species;Recurrence;Recurrent disease;refractory cancer;Reporting;Research Personnel;Resistance;Resource Sharing;Resources;response;Sampling;Serous;small molecule;spectroscopic imaging;spheroids;standard care;Systems Biology;targeted agent;targeted treatment;Technology;Testing;Therapeutic;therapeutic biomarker;therapy resistant;transcriptomics;Treatment Efficacy;treatment strategy;tumor;Tumor Debulking;two-photon;Unsaturated Fatty Acids;Woman;women's diagnosis;Work

PROJECT_TITLE: Understanding Metabolic Reprogramming in Platinum Resistant Ovarian Cancer


ORG_CITY: PITTSBURGH

ORG_NAME: VETERANS HEALTH ADMINISTRATION

ORG_STATE: PA

PHR: The long-term neurological functional deficits after traumatic brain injury (TBI) are major health concerns among veterans. Currently, no therapy is available to alleviate these neurological deficits. Recent research highlights the importance of immune responses in brain recovery. Regulatory T cells (Tregs) are a specialized subpopulation of immune cells that inhibit excessive immune responses under pathological conditions. This proposal will test the hypothesis that Tregs improve brain repair and promote long-term recovery after TBI by polarizing microglia/macrophages toward a beneficial phenotype that tempers inflammation and encourages tissue healing. This study will test the therapeutic potential of a protein complex composed of interleukin 2 (IL2) and IL2 antibodies, which increases endogenous Treg numbers and prevents the destructive sequelae of TBI. The results will shed light on the communication between immune cells and the injured brain, and are expected to inform future clinical immunotherapies against the long-term deficits suffered by TBI victims.

PI_NAMEs: HU, XIAOMING  (contact)

PROJECT_TERMS: Acute;Adult;Allogenic;Anti-Inflammatory Agents;Antibodies;Attenuated;B-Lymphocytes;Binding Sites;Brain;Brain Diseases;Brain Injuries;brain repair;brain tissue;Cell Count;Cell Therapy;Cells;Central Nervous System;Cerebrum;Chronic;Clinical;clinical application;clinical translation;Coculture Techniques;Cognitive;Cognitive deficits;Communication;Complex;controlled cortical impact;Data;Deterioration;effective therapy;Equilibrium;Exhibits;experimental study;Fostering;Future;gray matter;healing;Health;IL2RA gene;Immune;Immune response;Immune system;immunoregulation;Immunotherapy;Impairment;improved;In Vitro;in vitro testing;in vivo;in vivo evaluation;Infiltration;Inflammation;Inflammatory;Injections;Injury;Interleukin-2;Lesion;long term recovery;lymph nodes;Macrophage;Microglia;Modeling;Morbidity - disease rate;mortality;Mus;Nervous System Disorder;Nervous System Physiology;neuroinflammation;Neurologic;Neurologic Deficit;neurological recovery;neuroprotection;neurotoxic;new therapeutic target;novel;novel therapeutics;Oligodendroglia;Outcome;Pathologic;Peripheral;permissiveness;Phase;Phenotype;Play;prevent;protein complex;Recovery;Recovery of Function;Regulatory T-Lymphocyte;Reporting;Research;response;Role;sex;Spleen;Stroke;System;T-Cell Activation;T-Cell Depletion;T-Lymphocyte;Testing;Therapeutic Effect;therapeutic evaluation;Tissue Preservation;Tissues;Traumatic Brain Injury;Traumatic Brain Injury recovery;Veterans;white matter

PROJECT_TITLE: Novel immune therapy to promote functional recovery after traumatic brain injury


ORG_CITY: HINES

ORG_NAME: EDWARD HINES JR VA HOSPITAL

PHR: The Center for Disease Control and Prevention (CDC) classified Clostridioides difficile infection (CDI) as “Threat level urgent” and called for “urgent and aggressive action” to address a significant public health crisis in 2013 and 2019. The molecular epidemiology of CDI has changed drastically over the past 10 year and the epidemic strain, restriction endonuclease analysis (REA) group BI, PCR ribotype (RT) 027 has decreased significantly. However, REA group Y, which commonly correlates to RT 014 and 020[Y(RT014/020)], has remained a prominent group strain since the 1980s. Despite the endemic nature of Y(RT014/020), a detailed molecular analysis has never been completed. We propose to determine the prevalence and risk factors associated with the endemic Y(RT014/020) and the epidemic BI/RT027 group strains and perform a rigorous genomic analysis of Y(RT014/020) and BI/RT027 obtaining critical information to assess the endemic nature of Y(RT014/020) to assess our hypothesis that Y(RT014/020) resides within an unknown community reservoir.

PI_NAMEs: SKINNER, ANDREW MICHAEL (contact)

PROJECT_TERMS: Accounting;Address;Anaerobic Bacteria;Antibiotics;antimicrobial;bacterial genome sequencing;Centers for Disease Control and Prevention (U.S.);Cephalosporins;Cessation of life;Characteristics;Classification;Clinical;Clostridium difficile;Communities;Data;DNA Restriction Enzymes;Emerging infection;Epidemic;Epidemiologic Factors;Epidemiology;Evolution;Foundations;Genomics;Goals;Healthcare;healthcare-associated infections;Hospitals;Infection;innovation;K-Series Research Career Programs;Laboratories;military veteran;Molecular;Molecular Analysis;Molecular Epidemiology;Morbidity - disease rate;national surveillance;Nature;Pathogenesis;Pathologic;Patients;Phylogenetic Analysis;Polymerase Chain Reaction;Population;Prevalence;programs;protocol development;Public Health;Recording of previous events;Reproduction spores;Resistance;Ribotypes;Risk;Risk Factors;Scientist;Site;Source;stool sample;surveillance data;surveillance study;Surveys;Testing;Time;Training;trend;United States;United States Department of Veterans Affairs;Vertebral column;Veterans;virtual;Virulence Factors

PROJECT_TITLE: Epidemiological and Genomic Characteristics of the Widely Disseminated C. difficile Strain, REA Group Y


ORG_CITY: RICHMOND

ORG_NAME: VA VETERANS ADMINISTRATION HOSPITAL

ORG_STATE: VA

PHR: Non-alcoholic fatty liver disease (NAFLD) is becoming a globally prevalent disease, especially among US veterans. NAFLD and non-alcoholic steatohepatitis (NASH) are recognized as hepatic manifestations of metabolic syndrome. No effective therapy has been developed due to the incomplete understanding of the pathogenesis of this complex disease. BAs are important multifunctional signaling molecules. BA-mediated activation of sphingosine-1-phosphate receptor 2 (S1PR2) and sphingosine kinase 2 (SphK2) plays a critical role in hepatic lipid metabolism. Our proposed studies are aimed at elucidating the molecular mechanisms underlying BA-mediated activation of S1PR2/SphK2 in NASH disease progression. Completing this study will identify the potential novel cellular/molecular mechanisms in the initiation and progression of NAFLD/NASH and make a significant conceptual advance linking BAs and sphingolipids with metabolic diseases, which will create a fundamental base for developing novel therapies for NAFLD/NASH.

PI_NAMEs: ZHOU, HUIPING ROSE (contact)

PROJECT_TERMS: Anti-Inflammatory Agents;base;Bile Acids;Biological Process;cholangiocyte;Cirrhosis;clinically significant;Complex;Coupled;Data;Development;Diet;Disease;Disease Progression;dysbiosis;Dyslipidemias;effective therapy;Energy Metabolism;Evaluation;fatty acid metabolism;Fatty Liver;fatty liver disease;Fibrosis;G-Protein-Coupled Receptors;Gene Expression;Genes;glucose metabolism;GPBAR1 gene;HDAC1 gene;Hepatic;Hepatocyte;Heterogeneity;Homeostasis;Human;Immune system;Incidence;Inflammation;Inflammatory Response;inhibitor;Innate Immune Response;Insulin Resistance;Interferons;intrahepatic;Knockout Mice;Link;lipid metabolism;Lipids;Liver;liver inflammation;Macrophage;Maintenance;MAPK3 gene;Mediating;Metabolic Diseases;Metabolic stress;Metabolic syndrome;Mission;Modeling;Molecular;mouse model;Mus;Natural Immunity;non-alcoholic fatty liver disease;nonalcoholic steatohepatitis;novel;novel therapeutic intervention;novel therapeutics;Nuclear;Nuclear Receptors;Pathogenesis;Pathway interactions;Patients;Phosphorylation;Play;Prevalence;Primary carcinoma of the liver cells;Process;Proteins;Proto-Oncogene Proteins c-akt;receptor;Reporting;response;Role;Serum;Signal Transduction;Signaling Molecule;simple steatosis;single nucleus RNA-sequencing;Sphingolipids;sphingosine 1-phosphate;sphingosine kinase;Sphingosine-1-Phosphate Receptor;sugar;Testing;transcriptome sequencing;United States Department of Veterans Affairs;Veterans;Water;western diet

PROJECT_TITLE: Bile Acids and Sphingosine 1-Phosphate in Non-Alcoholic Steatohepatitis (NASH)


ORG_CITY: Decatur

ORG_STATE: GA

PHR: Almost 50% of women and 30% of men will suffer a fracture in their lifetimes. Fractures are a serious problem in aging Veterans and cause crippling disability requiring rehabilitation in up to 75% of individuals, loss of independence, and significant declines in quality of life. One year mortality after hip fracture in elderly veterans is 18% for women and 32% for men. Economic burden of fracture in the US is further projected to reach $25 billion/annum by 2025. As the largest integrated health care system in the US, the VA is on the front lines of fracture treatment and will have to absorb these ever-expanding medical needs and costs. In this project, we will use animal models to study two bone diseases that disproportionally affect Veterans, postmenopausal osteoporosis and bone loss cause by antiretroviral therapy against HIV. We will compare a novel therapeutic approach targeting early prevention of bone loss, to that of the current standard of care in which bone is regenerated after it has already been lost, a process that is only partly effective using currently available drugs.

PI_NAMEs: WEITZMANN, MERVYN NEALE (contact)

PROJECT_TERMS: absorption;Acquired Immunodeficiency Syndrome;Address;Affect;Aging;Anabolism;Animal Model;antiretroviral therapy;Anxiety;Biological Models;bisphosphonate;bone;Bone callus;Bone Density;Bone Diseases;bone health;bone loss;bone mass;Bone necrosis;bone preservation;bone quality;Bone Regeneration;bone repair;Bone Resorption;Bone structure;bone turnover;Cartilage;Chronic;chronic pain;Clinical;Clinical Management;Collaborations;cost;Diagnosis;dietary supplements;disability;Disease;disease model;Dual-Energy X-Ray Absorptiometry;Early Diagnosis;Early Intervention;Early treatment;Economic Burden;efficacy evaluation;Elderly;Ensure;Estrogen deficiency;Etiology;Femoral Fractures;Financial cost;Fracture;fracture risk;fragility fracture;Fright;Future;Goals;Health;Health Personnel;Healthcare Systems;high risk;Hip Fractures;HIV;HIV Infections;hormonal signals;Hospitals;Human;immune reconstitution;improved;in vitro Model;in vivo;Incidence;Individual;innovation;insight;Integrated Health Care Systems;Intervention;Jaw;male;Medical;men;Mental Depression;Modeling;Morbidity - disease rate;mortality;mouse model;Mus;Musculoskeletal Pain;Natural regeneration;novel;novel strategies;novel therapeutic intervention;Oral;Osteogenesis;Osteoporosis;Osteoporosis prevention;Osteoporotic;Outcome Measure;Ovariectomy;Participant;Patients;Pharmaceutical Preparations;pharmacologic;Pharmacotherapy;Phase;Phenotype;Postmenopausal Osteoporosis;Postmenopause;Pre-Clinical Model;prevent;Prevention;Prevention approach;Process;Prophylactic treatment;psychologic;PTH gene;Quality of life;Rehabilitation therapy;Rejuvenation;Reporting;Research;Research Personnel;Research Project Grants;research study;Resistance;Resort;Resources;side effect;Signal Pathway;skeletal disorder;Skeleton;Source;standard of care;stem;Techniques;Technology;Testing;Therapeutic;Time;tool;treatment effect;treatment strategy;Veterans;Weight-Bearing state;Woman

PROJECT_TITLE: BCCMA: Foundational Research to Act Upon and Resist Conditions Unfavorable to Bone (FRACTURE CURB): A stitch in time saves nine!


ORG_CITY: CLEVELAND

ORG_NAME: LOUIS STOKES CLEVELAND VA MEDICAL CENTER

ORG_STATE: OH

PHR: The decline in immunity with age contributes to poor response to vaccines, reduced recovery from new pathogens, increased cancer and a host of other morbidities. By 2050 it is predicted that 22% of the US population will be >65 years old. At the Cleveland VA Medical Center, around 1400 patients are enrolled in the Geriatric Clinic with an average age of 83 years old. During the 2018-2019 flu season people >65 accounted for 75% of deaths. We know that elderly have lower numbers of naïve T cells and increased inflammation but how these immune parameters contribute to immune dysfunction and poor response to immunization is unclear. Many facets of the immune system are interdependent and complex. Understanding which compartments contribute to poor vaccine response in the elderly, and identifying the pre-existing and unique immunological obstacles that must be overcome in the elderly population for an effective influenza vaccine are paramount for elderly veteran health.

PI_NAMEs: SHIVE, CAREY LYNN (contact)

PROJECT_TERMS: adaptive immune response;Adjuvant;Affect;Age;Age Years;Aging;Anti-Inflammatory Agents;Antibody Response;antigen-specific T cells;Antigens;arm;Attention;Autologous;B-Lymphocytes;Biological Assay;Biological Response Modifiers;Blocking Antibodies;CD4 Positive T Lymphocytes;Cell Count;Cell Physiology;Cells;Cessation of life;Chronic;Clinic;Complex;cytokine;Cytomegalovirus;Defect;Development;Effectiveness;Elderly;emerging pathogen;Environment;enzyme linked immunospot assay;Enzyme-Linked Immunosorbent Assay;Equilibrium;Flow Cytometry;FOXP3 gene;Frequencies;Future;Genetic Transcription;Health;Hemagglutination;Hemagglutinin;Hospitalization;Human Herpesvirus 4;human old age (65+);IL2 gene;IL2RA gene;Immune;Immune response;Immune system;Immune System Diseases;Immunity;Immunization;Immunologic Memory;Immunologics;Impairment;improved;in vitro Assay;Inflammation;Inflammatory;Influenza;Influenza vaccination;influenza virus vaccine;Innate Immune System;insight;Interferon Type II;Interleukin-6;Invaded;Lymphocyte Homing Receptors;Lymphopenia;Macrophage;Malignant Neoplasms;Measures;Medical center;monocyte;Morbidity - disease rate;novel;older patient;Outcome;Participant;participant enrollment;pathogen;Peptides;Peripheral;Peripheral Blood Mononuclear Cell;Persons;Phenotype;Plasma;Pneumonia;Population;Recovery;Regulation;Regulatory T-Lymphocyte;response;Role;Sampling;seasonal influenza;Serum;Specificity;Suggestion;T cell response;T memory cell;T-Lymphocyte;T-Lymphocyte Subsets;Testing;Transforming Growth Factor beta;Vaccination;vaccination outcome;vaccine response;Vaccines;Veterans;Viral Antigens;young adult

PROJECT_TITLE: Impact of preexisting immune profile in elderly on influenza vaccine response


ORG_CITY: OMAHA

ORG_NAME: OMAHA VA  MEDICAL CENTER

ORG_STATE: NE

PHR: Pseudomonas aeruginosa is a significant contributor to recalcitrant multi-drug resistant infections especially in immunocompromised and hospitalized patients. Multi-drug and totally drug resistant strains of P. aeruginosa are increasing threats that contribute to high mortality in these patients. Drug resistant infections are a threat to our Veteran population. Hence there is an urgent need to develop new strategies to combat P. aeruginosa and other resistant pathogens. The pathogenic profile of P. aeruginosa is related to its ability to secrete a variety of virulence factors and promote biofilm formation. Strategies that strengthen the ability of the host to inhibit these virulence factors would enhance host defenses and improve treatment. The goal of this proposal is to define novel molecular approaches to stimulate immune response through PGC-1 alpha activators (such as Metformin) to inhibit bacterial virulence and enhance host defenses. The results from these studies can be readily translated to human clinical trials since pioglitazone is already FDA approved for treatment of diabetes.

PI_NAMEs: SADIKOT, RUXANA T (contact)

PROJECT_TERMS: Agonist;airway epithelium;Attenuated;attenuation;Bacteria;Bioenergetics;Biogenesis;bronchial epithelium;Cell Physiology;clinical translation;Clinical Trials;combat;Data;Diabetes Mellitus;Drug resistance;Enzymes;Epithelial Attachment;Epithelial Cells;Epithelium;factor A;FDA approved;Functional disorder;Funding;gain of function;Genes;Genetic;Glycolysis;Goals;Health;Hospitalization;Host Defense;Host resistance;Human;Hydrolysis;Immune;immune function;Immune response;Immunocompromised Host;Immunologic Stimulation;Impairment;improved;improved outcome;In Vitro;in vivo;Infection;Inflammasome;Inflammatory Response;Innate Immune Response;insight;Ligands;lipid mediator;loss of function;Lung;Lung immune response;Lung infections;Metformin;Microbial Biofilms;migration;military veteran;Mitochondria;Molecular;mortality;mouse model;mtTF1 transcription factor;Multi-Drug Resistance;Mus;mutant;novel;novel therapeutic intervention;novel therapeutics;overexpression;pathogen;Pathogenesis;Pathogenicity;Pathway interactions;Patients;Pharmaceutical Preparations;pharmacologic;Pioglitazone;Post-Transcriptional Regulation;PPAR gamma;preclinical study;prevent;Production;Pseudomonas aeruginosa;Pseudomonas aeruginosa infection;Pseudomonas aeruginosa pneumonia;Reactive Oxygen Species;Resistance;resistant strain;response;Role;shift work;Signal Transduction;small molecule;Testing;tool;transcription factor;Transcriptional Regulation;Translating;Type III Secretion System Pathway;Veterans;Virulence;Virulence Factors;Virulent;Work

PROJECT_TITLE: PGC-1 alpha in Lung Immune Response


ORG_CITY: NASHVILLE

ORG_STATE: TN

PHR: Osteoporosis and hypertension are major health concerns that lower lifespan and hinder the ability to remain independent and active. Veterans are susceptible to both diseases, and clinical studies indicate that the progression of these two chronic conditions occur at the same time suggesting they are linked. To identify new strategies in the prevention of fragility fractures, the devastating consequence of osteoporosis, this project will investigate common pathways by which hypertension activates the bone marrow to cause bone loss and weaken bone. By using established pre-clinical models of this disease using aged animals, by collaborating with other Veteran Affairs research investigators to share ideas and unify rigorous outcome measures, and by targeting secondary causes of osteoporosis, this project is well positioned to identify a new and translatable strategy for improving bone health, namely increasing the fracture resistance of bone.

PI_NAMEs: NYMAN, JEFFRY STEPHEN (contact)

PROJECT_TERMS: Address;Adult;Affect;Age;age related;Age Years;aged;Aging;Amlodipine;Anabolism;Angiotensin II;animal old age;Blood;Blood Pressure;blood pressure reduction;Blood Vessels;bone;Bone callus;bone cell;bone fracture repair;bone health;bone loss;Bone Marrow;bone mass;bone quality;Bone Regeneration;bone repair;Bone Resorption;bone strength;cadherin 5;Calcium Channel Blockers;Cartilage;Catecholamines;Cell Count;Cell Line;Cells;Chronic;Chronic Disease;Clinical;Clinical Management;Clinical Research;Collaborations;Combined Modality Therapy;cytokine;Cytoprotection;dentin matrix protein 1;Diabetes Mellitus;Diagnosis;Disease;disease model;DOCA;Dual-Energy X-Ray Absorptiometry;Early Diagnosis;Endothelial Cells;Engineering;Ensure;Estrogen deficiency;Estrogens;Euthanasia;experimental study;Female;Fracture;fracture risk;fragility fracture;Gene Expression;Gene Proteins;Goals;Gonadal Steroid Hormones;Health;Health Personnel;Hip Fractures;hormonal signals;Hospitals;Hypertension;hypertensive;Implant;improved;in vitro Model;in vivo;inducible Cre;Inflammatory;inhibitor;Injections;innovation;insight;Knock-out;Lead;life span;Link;loss of function;LoxP-flanked allele;Macrophage Colony-Stimulating Factor;Macrophage Colony-Stimulating Factor Receptor;male;Marrow;Mechanics;Mediator;Medical;Metabolism;military veteran;Modeling;Monitor;Morbidity - disease rate;mortality;mouse Cre recombinase;mouse model;Mouse Strains;Mus;Musculoskeletal Pain;normotensive;novel;novel strategies;novel therapeutic intervention;old mice;Operative Surgical Procedures;Orchiectomy;Osteoblasts;osteoclastogenesis;Osteocytes;Osteogenesis;Osteoporosis;Osteoporosis prevention;osteoporosis with pathological fracture;Outcome;Outcome Measure;Ovariectomy;Pathway interactions;Patients;Population;Positioning Attribute;pre-clinical;Pre-Clinical Model;Predisposition;Prevalence;prevent;Prevention;Prevention approach;Production;protein expression;PTH gene;Research;Research Personnel;research study;Resistance;Risk;Role;Services;sex;side effect;Signal Pathway;Signal Transduction;Sodium Chloride;Source;Tail;Tamoxifen;Techniques;Testing;Testosterone;Therapeutic;Time;Tissues;tool;translatable strategy;translational study;treatment effect;treatment group;treatment strategy;United States Department of Veterans Affairs;urinary;Urine;Veterans

PROJECT_TITLE: BCCMA: Foundational Research to Act Upon and Resist Conditions Unfavorable to Bone (FRACTURE CURB): Role of Hypertension in Favoring Osteoporosis


PHR: Increased incidence of lymphoma over the past decade is a major concern for our aging Veterans. While clinical advances have been made in diffuse large B cell lymphoma (DLBCL) treatment, there is still high mortality (~50%) in afflicted individuals with R-CHOP therapy due to frequent occurrence of relapsed/refractory cases and limited clinical efficacy in co-morbid patients. Clearly, there is an unmet medical need for improved, less toxic therapy for lymphoma. Our initial observations suggest that enhanced FASN activity functionally regulates the eIF4B -driven protein translational machinery in DLBCL cells. Extending our work, our preliminary data indicate that PARK2 ubiquitinates eIF4B in a FASN-dependent manner. Furthermore, we observed that eIF4B is an LKB1 substrate, positioning the protein as a key therapeutic target. Importantly, we have generated complementary mouse models that will enhance our understanding of the pathophysiological impact of eIF4B in DLBCL providing a rational basis for developing novel molecular targets.

PI_NAMEs: GARTENHAUS, RONALD B (contact)

PROJECT_TERMS: 70-kDa Ribosomal Protein S6 Kinases;Accounting;Actins;activated B cell like;Address;Aging;B-Cell Development;B-Lymphocytes;BCL2 gene;BCL6 gene;Biochemical;Bioenergetics;c-myc Genes;CD19 gene;Cell Compartmentation;Cell Line;Cell Maturation;Cell model;Cell Ontogeny;Cell Separation;Cells;Classification;Clinic;Clinical;Clinical Data;clinical efficacy;Clinical Research;clinically relevant;Co-Immunoprecipitations;comorbidity;Cyclophosphamide;Cytomegalovirus;Data;Data Set;Dependence;Development;Diagnostic;Disease Resistance;Doxorubicin;Engineering;Enzymes;Essential Genes;Eukaryotic Initiation Factor-4E;Eukaryotic Initiation Factors;Event;experimental study;fatty acid metabolism;Fatty-acid synthase;Functional disorder;Gene Expression;Generations;Genes;genetic regulatory protein;genetic signature;Globin;Growth;Hand;High Fat Diet;Homeostasis;Human;Hybrids;Hyperactivity;Impairment;improved;improved outcome;in vivo;Incidence;Individual;insight;Insulin;Knock-out;Laboratories;large cell Diffuse non-Hodgkin's lymphoma;Ligase;LoxP-flanked allele;Luciferases;Lymphoma;Lymphoma cell;Lymphomagenesis;Malignant lymphoid neoplasm;Malignant Neoplasms;Mediating;Medical;Metabolic;metabolome;Modification;Molecular;Molecular Target;mortality;mouse model;Multi-Drug Resistance;Mus;mutant;neoplastic cell;Newly Diagnosed;Non-Hodgkin's Lymphoma;novel;Nutrient;obese patients;Oncogenes;Oncogenic;Output;overexpression;Parkinson Disease;Partner in relationship;Pathway interactions;Patients;Peptide Hydrolases;pharmacologic;Phenocopy;Phosphorylation;Phosphotransferases;Physiological;PIK3CG gene;Polyubiquitination;Positioning Attribute;posttranscriptional;pre-clinical;preclinical study;Prednisone;Progression-Free Survivals;Proliferating;promoter;Proteins;Publishing;Refractory;Relapse;Reporting;Research Personnel;Ribosomal Protein S6 Kinase;rituximab;Role;Seminal;Signal Transduction;spatiotemporal;standard care;STK11 gene;Stress;Structure of germinal center of lymph node;success;Survival Rate;targeted agent;Therapeutic;therapeutic candidate;Therapeutic Intervention;therapeutic target;Tissues;tool;Toxic effect;Transgenic Mice;Transgenic Organisms;Translations;tumor growth;Tumor Suppressor Proteins;Ubiquitin;ubiquitin isopeptidase;ubiquitin-protein ligase;ubiquitin-specific protease;Ubiquitination;United States;Validation;Veterans;Vincristine;Work

PROJECT_TITLE: Molecular Characterization of elF4B


ORG_CITY: PORTLAND

ORG_NAME: PORTLAND VA MEDICAL CENTER

ORG_STATE: OR

PHR: Parkinson's disease is a growing burden for Veterans without a cure and usually without a known cause. For Veterans that have Parkinson's disease, we know the disease is usually widespread decades before diagnosis, including in the skin, and that catching the disease earlier could help us understand what causes the disease, how it spreads through the body, and how to find a cure. This project will map Parkinson's disease before diagnosis by using resources at the VA and a “big data” approach. The project will combine findings from biopsies and clinical care performed years before diagnosis with genetic studies in the Million Veteran Program. By combining these pieces of information, we hope to create a comprehensive description about how a Veteran's genetic background and symptoms relate to what's happening in his or her cells and tissues. By doing so we also hope to understand different types of Parkinson's disease. A better understanding of early Parkinson's disease should help in developing markers of disease and ultimately a cure.

PI_NAMEs: SCOTT, GREGORY DAVID (contact)

PROJECT_TERMS: Age;alpha synuclein;Big Data;biobank;Biological Assay;Biological Markers;Biopsy;Cataloging;Cells;Characteristics;Clinical;clinical care;Clinical Data;clinical subtypes;cohort;Data;Data Set;Databases;Dermatophytoses;Diagnosis;diagnostic value;differential expression;Disease;disease diagnosis;Disease Marker;Disease Progression;disorder subtype;Enrollment;experimental study;Freezing;Gene Frequency;Genetic;Genetic Risk;Genetic study;genetic variant;Genome;genome wide association study;Genomics;Healthcare;Healthcare Systems;Histopathology;Immunofluorescence Immunologic;indexing;Individual;innovation;insight;Knowledge;Link;male;Maps;Measures;Medical;Medical Records;Methods;Microscopy;Neurons;novel;Parkinson Disease;Participant;Pathogenesis;Pathologic;Pathology;Patients;Peripheral;Prevalence;programs;Resources;risk variant;Seborrheic dermatitis;segregation;Services;Skin;skin biopsy;skin disorder;Skin Tissue;Sleep;Sleep Disorders;Specimen;Subgroup;Susceptibility Gene;Symptoms;synuclein;synucleinopathy;Testing;Time;Tissues;Veterans;Veterans Health Administration

PROJECT_TITLE: Early pathogenesis and diagnosis of Parkinsons Disease in peripheral tissues


ORG_CITY: Aurora

ORG_NAME: VA EASTERN COLORADO HEALTH CARE SYSTEM

ORG_STATE: CO

PHR: Antibiotic resistant Gram-negative bacterial infections are associated with high rates of morbidity and mortality around the globe, disproportionally affecting the men and women actively serving in the armed forces, veterans, and patients in VA hospitals. Despite the health crisis associated with the rampant occurrence of antibiotic resistant bacterial isolates, only 24 new antibiotics have been approved since 1987. Most newer antibiotics are modifications or reformulations of existing drugs. None of the recently approved antibiotics have novel mechanisms of action. We have generated new chemical entities that bind to and inhibit a transcriptional factor conserved in bacteria but absent in humans. One of our novel antibiotics protects mice against a common and often life-threatening bacterial pathogen. Our proposal to synthesize improved transcriptional inhibitors with potent antimicrobial activity in animal models of infection will help with the rational design of the next generation of antibiotics.

PI_NAMEs: VAZQUEZ-TORRES, ANDRES  (contact)

PROJECT_TERMS: Abscess;absorption;Acute;Adsorption;Affect;analog;Animal Model;Animals;Antibiotic Resistance;antibiotic resistant infections;Antibiotic Therapy;Antibiotics;antimicrobial;Appearance;Award;Azoles;Bacteria;Bacterial Antibiotic Resistance;Binding;Biochemistry;Bioinformatics;Biological;Biological Assay;Cell model;Cessation of life;clinically relevant;Communicable Diseases;Dangerousness;Derivation procedure;Development;Disease;DNA-Directed RNA Polymerase;Drug Kinetics;Endowment;enteric pathogen;Evaluation;Excretory function;Exhibits;Family;Formulation;Funding;General Population;Genetic Transcription;Goals;Gram-Negative Bacteria;Gram-Negative Bacterial Infections;Grant;Health;Hospitals;Human;improved;In Vitro;Infection;inhibitor;Investigation;Legal patent;Life;men;Metabolic;Metabolism;Military Personnel;military veteran;Modeling;Modification;Molecular Target;Morbidity - disease rate;mortality;mouse model;Mus;Necrosis;new chemical entity;next generation;nitrosative stress;non-typhoidal Salmonella;novel;Oxidative Stress;pathogen;Pathogenesis;pathogenic bacteria;Patients;Permeability;Pharmaceutical Preparations;Pharmacodynamics;pharmacokinetics and pharmacodynamics;Phylogenetic Analysis;Play;prevent;programs;Progress Reports;Property;Proteins;Publishing;rational design;Rattus;response;Rod;Role;Salmonella;Salmonella enterica;Salmonella infections;scaffold;Structure-Activity Relationship;Testing;Therapeutic;therapeutic effectiveness;therapeutic evaluation;Toxic effect;transcription factor;Translations;Veterans;Virulence;Woman;World Health Organization

PROJECT_TITLE: Development of DksA-targeted Antibiotics for Treatment of Gram-negative Infections


PHR: Cardiac disease, is a common cause of death in PKD patients. Study of the mechanisms of cardiac hypertrophy, beyond hypertension, is an unmet need. Furthermore, testing of novel agents that block mTORC1/2 outputs e.g. 2nd, 3rd and 4th generation mTORC1/2 inhibitors and palmitate conjugated ASOs that vigorously penetrate heart muscle, is an unmet need in cardiac hypertrophy in general as well as PKD specifically. The proposal uses genetic and pharmacological interventions to explore unanswered questions of mTORC1/2 signaling in cardiac hypertrophy: 1) The effect of genetic knockout, ASO therapies and pharmacological inhibition of different components of the 4E-BP1/eIF4E pathway. 2) The effect of new 2nd, 3rd and 4th generation mTOR inhibitors, 3) The effect of pharmacological inhibition/activation of mTORC2 and mTORC2 outputs, Akt or PKCα. 4) The effect of mTORC1/2 inhibition on autophagic flux in the heart.

PI_NAMEs: EDELSTEIN, CHARLES LOUIS (contact)

PROJECT_TERMS: Antisense Oligonucleotide Therapy;Apoptosis;Attention;Autophagocytosis;Autosomal Dominant Polycystic Kidney;Binding;Blood Pressure;Cardiac;Cause of Death;CD3 Antigens;CD8B1 gene;Cell Count;Cells;clinical practice;Clinical Research;Complex;Cyclic AMP;Cyst;cytotoxic;Data;Development;EIF4EBP1 gene;experimental study;FRAP1 gene;Functional disorder;Future;Generations;Genetic;Genetic study;Glucose;Glucose tolerance test;Goals;Growth;Heart;Heart Diseases;Heart Function Tests;Heart Hypertrophy;human disease;Hypertension;Immune;improved;in vivo;inhibition of autophagy;inhibitor;insight;Intervention;kinase inhibitor;Knock-out;Link;Lipids;Mediating;Modeling;mouse model;mTOR Inhibitor;Mus;Muscle Cells;Myocardium;novel;novel therapeutics;Output;overexpression;Palmitates;Pathway interactions;Patients;Penetration;pharmacologic;Phosphorylation;Phosphorylation Inhibition;Plasma;pre-clinical;PRKCA gene;Proteins;Proto-Oncogene Proteins c-akt;Protocols documentation;Publishing;restraint;Role;side effect;Signal Pathway;Signal Transduction;Sirolimus;Structure;T-Lymphocyte;targeted agent;Testing;Therapeutic;Therapeutic Effect;Translations;Weight

PROJECT_TITLE: mTORC1/2 Signaling in the Heart in Autosomal Dominant Polycystic Kidney Disease (ADPKD)


ORG_CITY: MADISON

ORG_NAME: WM S. MIDDLETON MEMORIAL VETERANS HOSP

ORG_STATE: WI

PHR: The goal of this study is to i) determine the therapeutic efficacy of a simultaneous targeting of PLK1 and NOTCH, two biologically-informed novel melanoma targets, for the management of metastatic and drug- resistant melanoma, and ii) identify novel signaling mechanisms associated with their biological responses, using human-relevant melanoma mouse models. This pre-clinical study is expected to provide mechanistic insights and rationale for clinical testing of a new combination of drugs to obtain superior response against melanoma. Our proposed research is relevant and significant to the Veterans because melanoma is the fifth most diagnosed malignancy among Veterans, and the fact that the US military has been engaged, in missions all over the world, many US military personnel, who are deployed to high ultraviolet (UV) climates in tropical and subtropical zones are potentially at a higher risk for melanoma.

PI_NAMEs: AHMAD, NIHAL  (contact)

PROJECT_TERMS: ABCB1 gene;ABCC1 gene;Affect;angiogenesis;anti-tumor immune response;ANXA5 gene;Biological;Blood Vessels;BRAF gene;cancer type;Cell Cycle;Cell Cycle Regulation;Cell Line;Cell Proliferation;Cells;Characteristics;chemotherapy;Climate;Clinical;Clinical Management;combinatorial;Combined Modality Therapy;Data;Development;Diagnosis;Disease;Disease Progression;Drug resistance;efficacy evaluation;Embryo;Epithelium;Evolution;Extracellular Matrix;Family member;FDA approved;gamma secretase;Gene Expression Profiling;Genes;Genetic Engineering;genetic manipulation;Goals;Growth;Healthcare;high risk;Human;human disease;Immune checkpoint inhibitor;Immunotherapy;improved;in vivo;inhibitor;insight;Laboratories;Link;Malignant Neoplasms;MEKs;Melanoma;Melanoma Cell;Melanoma patient;melanomagenesis;Mesenchymal;Metastatic Melanoma;Military Personnel;Mission;Mitosis;Modeling;mouse model;Mutation;nano-string;Neoplasm Metastasis;Neoplasms;NOTCH1 gene;novel;novel drug combination;Oncogenic;Outcome;overexpression;Pathway interactions;patient derived xenograft model;Patients;Pharmaceutical Preparations;Phosphopeptides;Play;PLK1 gene;preclinical study;Preclinical Testing;Progression-Free Survivals;Proliferating;Protein-Serine-Threonine Kinases;Proteins;Proteome;Proteomics;Publishing;Relapse;Reporting;repository;Research;research clinical testing;Resistance;Resistance development;response;Role;Sampling;Serine;Signal Transduction;small molecule;success;survivin;targeted treatment;Techniques;Testing;Therapeutic;therapeutic target;therapy resistant;Tissues;transcriptome sequencing;Treatment Efficacy;Treatment outcome;treatment response;tumor;Tumor Markers;tumor progression;ultraviolet;United States National Institutes of Health;Validation;Veterans;Work

PROJECT_TITLE: Combined inhibition of PLK1 and NOTCH for melanoma management


ORG_CITY: MIAMI

ORG_NAME: MIAMI VA HEALTH CARE SYSTEM

ORG_STATE: FL

PHR: Opioid use disorder (OUD) has reached an epidemic level in the United States. After combat deployment, 15% of veterans use opioids compared to 4% of the general population. Opioid dependence is a chronic and relapsing disease and is characterized by compulsive drug seeking and use. Higher daily opioid dose use for analgesic effect may lead to opioid dependence. The proposal will examine new mechanisms of glia-neuron interaction, helping develop strategies aimed at therapeutic interventions of opioid withdrawal for both the general population and veterans.

PI_NAMEs: HAO, SHUANGLIN  (contact)

PROJECT_TERMS: addiction;Analgesics;Astrocytes;Behavior;Biological Assay;Biological Markers;Brain Stem;cell type;Chronic;Chronic Disease;Clinical;combat;conditional knockout;Data;Development;Disease;Dose;economic cost;Economics;effective therapy;Epidemic;Epigenetic Process;EZH2 gene;Future;Gene Expression;Gene Silencing;Gene Transfer;General Population;Genetic;Genetic Transcription;Goals;Housing;Individual;insight;Knockout Mice;LCN2 gene;Lead;Mediating;Mental Health;Methylation;midbrain central gray substance;Mission;Mitochondria;Molecular;Morphine;mortality risk;Mus;Nervous System Trauma;Neuroglia;neuroinflammation;Neurons;new therapeutic target;NF-kappa B;novel therapeutics;Opiate Addiction;Opioid;opioid abuse;opioid epidemic;opioid use;opioid use disorder;opioid withdrawal;overdose death;overdose risk;overexpression;p65;Pathogenesis;Pathway interactions;Patient Care;Patients;Performance at work;Pharmaceutical Preparations;pharmacologic;physical conditioning;Physical Dependence;Pilot Projects;prescription opioid;promoter;Psychological Dependence;receptor;Recurrent disease;Regulation;Relapse;Role;Sirtuins;Social Functioning;Substance Withdrawal Syndrome;Testing;Therapeutic Intervention;TLR4 gene;transcription factor;United States;United States Department of Veterans Affairs;Veterans;Veterans Health Administration;Viral;Withdrawal;Work

PROJECT_TITLE: The molecular mechanisms of astrocytes-neurons interaction in the morphine use disorder


PHR: Diabetes is a costly and complex chronic illness and a serious public health problem, responsible for a host of complications that significantly decrease healthy lifespan. The Veteran population has a significantly increased prevalence of diabetes as compared to the general population, making diabetes a critical problem in Veterans’ health. The underlying issue in diabetes is the failure of the pancreas cells to release enough of the hormone, insulin, into the bloodstream to properly control blood sugar levels. The aims of this proposal are to characterize emerging cellular targets to promote pancreatic cell health and proper insulin release, ultimately improving the care and treatment of diabetic Veterans.

PI_NAMEs: KIMPLE, MICHELLE E (contact)

PROJECT_TERMS: Adenylate Cyclase;Aging;Agonist;Ally;Alpha Cell;antagonist;Arachidonic Acids;autocrine;Beta Cell;Blood Circulation;Blood Glucose;Caring;Cell Death;Cell Physiology;cell type;Cells;cellular targeting;Chemicals;Child;Cholecystokinin;Chronic Disease;Compensation;Complex;cost;Coupled;Critical Pathways;Cyclic AMP;Cytoplasm;Data;Diabetes Mellitus;diabetes mellitus therapy;Diabetes prevention;diabetes risk;diabetic;diabetic patient;diabetogenic;Dinoprostone;Etiology;Exposure to;Failure;Functional disorder;functional loss;Gene Expression Profile;General Population;Genes;Genetic;GLP-I receptor;glucagon-like peptide 1;Glucose;Goals;Growth;GTP-Binding Protein alpha Subunits;GTP-Binding Proteins;Health;healthspan;Hormones;Human;Hyperglycemia;Immune;improved;incretin hormone;Individual;innovation;Insulin;insulin secretion;islet;Islet Cell;Knock-out;Knockout Mice;Life Style;lifetime risk;Link;Mediating;Membrane;Metabolic;metabolome;Methods;military veteran;Molecular;Mus;Non obese;non-diabetic;Non-Insulin-Dependent Diabetes Mellitus;novel;Obesity;Organ Donor;Osmosis;Pancreas;paracrine;Paracrine Communication;Pathway interactions;patient population;Pharmaceutical Preparations;pharmacologic;Pre-Clinical Model;Prediabetes syndrome;preservation;Prevalence;prevent;Process;Production;programs;Protein Isoforms;Public Health;Pump;receptor;Regulation;Research;Residual state;Resistance;RNA Splicing;Role;Second Messenger Systems;Signal Pathway;Signal Transduction;Signaling Molecule;Stimulus;Structure of beta Cell of islet;Sulfonylurea Compounds;Testing;Therapeutic;therapeutic target;Tissues;Variant;Veterans;Work

PROJECT_TITLE: G protein mediated mechanisms of beta-cell compensation and failure in type 2 diabetes


PHR: The proposed studies will investigate the role of the epidermal growth factor receptor (EGFR) and its ligand, HB-EGF in mediation of acute and chronic kidney injury. The studies will investigate role and mechanism of EGFR activation in renal pericytes and resident fibroblasts in response to acute kidney injury. In addition, the studies will investigate renal macrophage-fibroblasts interactions. The studies will also investigate the role of macrophage HB-EGF expression to mediate renal epithelial repair and regeneration following acute kidney injury. In addition, the studies will investigate the potential role of macrophage HB-EGF to activate the ErbB4 receptor to prevent development of subsequent tubulointerstitial fibrosis. Therefore, these studies will provide new and important insights into mechanisms of kidney injury and repair.

PI_NAMEs: HARRIS, RAYMOND C. (contact)

PROJECT_TERMS: Acute;Acute Renal Failure with Renal Papillary Necrosis;Amphiregulin;betacellulin;Binding;Chronic;Chronic Kidney Failure;Collagen;Development;DTR gene;EGF gene;Epidermal Growth Factor Receptor;epigen;Epiregulin;Epithelial Cells;epithelial repair;Epithelium;epithelium regeneration;ErbB Receptor Family Protein;ERBB2 gene;ErbB4 gene;extracellular;Extracellular Matrix;Fibroblasts;Fibrosis;Goals;Incidence;Inflammatory;Injury;injury and repair;Injury to Kidney;Innate Immune System;insight;interstitial;Ischemia;ischemic injury;Kidney;kidney repair;Left;Ligand Binding Domain;Ligands;Macrophage;Mediating;Mediation;Mediator;Medical;migration;military veteran;Morbidity - disease rate;mortality;Mus;Myelogenous;Myeloid Cells;Myofibroblast;nephrogenesis;Neuregulin 1;neutrophil;novel;paracrine;Pericytes;Phenotype;Population;prevent;Prevention;Process;Production;Proliferating;promoter;receptor;Receptor Activation;Recovery;Recovery of Function;recruit;renal damage;renal epithelium;Reperfusion Injury;Reperfusion Therapy;response;Role;Stromal Cells;System;Transforming Growth Factor alpha;Ureteral obstruction

PROJECT_TITLE: Mechanisms of Adaptive and Maladaptive Response of Renal Epithelium to Injury


PHR: The mortality rate for acute respiratory distress syndrome (ARDS) remains unacceptably high (~40%), particularly in light of the COVID-19 pandemic (ARDS is the leading cause of death among COVID patients). There are no FDA-approved treatments for ARDS. Overwhelming data demonstrate that ARDS patient outcomes are significantly worse among the elderly population, however, we do not yet understand the mechanisms that account for this age-associated predisposition. The proposed studies seek to better understand what “goes awry” in aging, and propose that specifically targeting defective mechanisms in aging may be the key to improving outcomes for elderly ARDS patients.

PI_NAMEs: HECKER, LOUISE  (contact)

PROJECT_TERMS: Acute;Acute Lung Injury;Acute Respiratory Distress Syndrome;age related;age-related disease;aged;Aging;Antioxidants;Cause of Death;Cells;Clinical Trials;cohort;COVID-19 pandemic;COVID-19 patient;Data;Death Rate;Development;Eko;Elderly;Endothelial Cells;Endothelium;Enzymes;epidemiologic data;Exhibits;Failure;FDA approved;Functional disorder;Generations;Genetic;high risk population;Impairment;improved;improved outcome;in vivo;Incidence;Inflammatory;Inflammatory Response;Injury;insight;Knock-out;Light;Link;Lung;lung injury;Mediating;military veteran;Molecular Weight;mortality;multicatalytic endopeptidase complex;Mus;Mutagenesis;NADPH Oxidase;novel;novel marker;old mice;Outcome;overexpression;Oxidants;Oxidation-Reduction;oxidative damage;Oxidative Stress;Pathogenesis;Pathologic;Patient-Focused Outcomes;Patients;Permeability;pharmacologic;Pharmacotherapy;Phenotype;Plasma;Play;Population;Post-Translational Protein Processing;pre-clinical;Predisposition;Production;prognostic indicator;Reactive Oxygen Species;Reporting;Resolution;response;RNA Splicing;Role;sample collection;senescence;Severities;Signal Transduction;Source;survival outcome;System;Testing;Therapeutic;therapeutic development;therapy development;Tissues;Ubiquitin;Variant

PROJECT_TITLE: Aging and ARDS: Novel Mechanistic Role of Nox4/D in Age-Dependent Barrier Dysfunction


PHR: End stage kidney disease is a major cause of morbidity and mortality for Veterans. One of the hallmarks of end stage kidney disease is tubulointerstitial fibrosis, characterized by abnormal accumulation of extracellular matrix along injured tubules leading to the loss of functioning kidneys. The goal of this VA Merit renewal is to understand the mechanisms that underlie the modulation of matrix turnover in injured kidneys to devise more effective therapies to prevent tubulointerstitial fibrosis and in turn loss of kidney function. We will focus on the receptor tyrosine kinase RON and its target TGF-β receptor II (TβRII). We show that: 1) RON contributes to kidney injury and fibrosis by promoting TGF-β secretion and by phosphorylating TβRII on tyrosine residues thus potentiating TβRII-mediated pro-inflammatory and pro-fibrotic signaling; and 2) inhibition of RON decreases TβRII tyrosine phosphorylation, TGF-β-mediated signaling, inflammation, and collagen production. Thus, RON-induced activation of TβRII represents a novel mechanism to selectively enhance TGF-β-mediated kidney injury.

PI_NAMEs: POZZI, AMBRA  (contact)

PROJECT_TERMS: Acute;Acute Renal Failure with Renal Papillary Necrosis;Atrophic;Binding;Biological Assay;Cell Culture Techniques;cell type;Cells;Chronic Kidney Failure;Chronic Phase;clinically relevant;Collagen;Collagen Receptors;constitutive expression;crizotinib;cytokine;Cytoplasmic Tail;Data;defined contribution;Deposition;design;Development;Disease Progression;effective therapy;End stage renal failure;Epithelial Cells;Epithelium;Extracellular Matrix;Fibroblasts;Fibrosis;Genetic;Goals;Grant;Homeostasis;IL18 gene;In Vitro;in vivo;Infiltration;Inflammation;Inflammatory;inhibitor;injured;Injury;Injury to Kidney;Integrins;interleukin-18 binding protein;interstitial;Kidney;Kidney Diseases;kidney epithelial cell;kidney fibrosis;Ligands;loss of function;Macrophage;MADH3 gene;Mediating;Mediator;Modeling;Molecular;Morbidity - disease rate;mortality;Mus;Myofibroblast;novel;novel strategies;Organ;Organ failure;overexpression;Pathogenesis;Pathway interactions;pharmacologic;Phenotype;Phosphorylation;Phosphotransferases;Play;prevent;Prevention;Process;Production;Profibrotic signal;Protein Tyrosine Kinase;Protein Tyrosine Phosphatase;Proteins;receptor;Receptor Protein-Tyrosine Kinases;Receptor Serine/Threonine Kinase;Regulation;Renal function;response;Role;Signal Transduction;small molecule;STAT3 gene;T-cell protein tyrosine phosphatase;Tail;Testing;Transforming Growth Factor beta;Transforming Growth Factor Beta 2;Transforming Growth Factor beta Receptors;Translating;Tubular formation;Tyrosine;Tyrosine Phosphorylation;Veterans

PROJECT_TITLE: Molecular Mechanisms of Kidney Fibrosis


ORG_CITY: IOWA CITY

ORG_NAME: IOWA CITY VA MEDICAL CENTER

ORG_STATE: IA

PHR: Cytomegalovirus (CMV) infection takes a toll on the life and health of thousands of Veterans because the currently available antiviral drugs are woefully inadequate. The Institute of Medicine estimates an annualized healthcare cost savings of $1-4 billion if CMV infection could be prevented. A CMV vaccine that effectively prevents infection is unlikely to be realized in the next decade. Thousands of Veterans already have CMV within them that has re-activated from dormancy to produce disease. This motivates a search for alternative ways of blocking CMV infection. Our research goal is to deactivate CMV before it starts replicating. By studying how CMV activates its gene expression program for replication, we aim to identify vital targets susceptible to precision-guided pharmacologic agents that effectively neutralize the virus. We will also discover previously unknown mechanisms of gene expression control that is broadly relevant to other viruses and many human diseases.

PI_NAMEs: MEIER, JEFFERY L (contact)

PROJECT_TERMS: Acute;Address;Affect;Anti-viral Agents;Binding;bioinformatics pipeline;Biological Assay;Cell Line;Cell model;cell type;ChIP-seq;Chromatin;Chromatin Structure;Collaborations;Complex;Congenital Abnormality;Cost Savings;Cytomegalovirus;Cytomegalovirus Infections;Cytomegalovirus Vaccines;Data;design;Disease;DNA biosynthesis;DNA Polymerase II;DNA Sequence;Drug resistance;Environment;Fibroblasts;functional genomics;gammaherpesvirus;Gene Expression;Gene Expression Regulation;Genes;Genetic Engineering;Genetic Transcription;genetically modified cells;Genome;genome-wide;Genomic approach;genomic locus;Goals;Health;Health Care Costs;Herpesviridae;Hour;Human;human disease;Human Herpesvirus 4;Human Herpesvirus 6;human model;Immune system;Impairment;Individual;Infection;Infection prevention;Inflammation;Institute of Medicine (U.S.);Knowledge;Life;Maps;Mass Spectrum Analysis;member;Modeling;mortality risk;new therapeutic target;novel therapeutics;Nucleosomes;Oncogenic;Output;Pathway interactions;Pattern;pharmacologic;Population;Precision Run-On Sequencing;Predisposition;prevent;Price;Productivity;programs;promoter;Promoter Regions;Protein Isoforms;Regulation;Research;Resolution;Role;Sarcoma;Signal Transduction;Site;System;Taxes;Techniques;Technology;Testing;Therapeutic;Therapeutic Intervention;tool;Toxic effect;Transcript;transcription factor;Transcription Initiation;Veterans;Viral;viral DNA;Viral Drug Resistance;virology;Virus;Virus Activation;Virus Diseases;virus testing

PROJECT_TITLE: Mechanisms Regulating Cytomegalovirus


ORG_CITY: NORTHPORT

ORG_NAME: NORTHPORT VA MEDICAL CENTER

ORG_STATE: NY

PHR: The CDC estimates more than 30 million Americans have chronic kidney disease (CKD), with a disproportionate burden on U.S. Veterans (prevalence a third higher than the general population), and we have no sustainable therapeutic strategies to prevent or reverse CKD. Acute kidney injury (AKI), despite initial renal recovery, is a major risk factor for CKD. The proximal tubule (PT) is the primary target in AKI due to its high susceptibility to ischemia and DNA-damaging nephrotoxins such as chemotherapeutic agents. Mitochondrial fatty acid b-oxidation (FAO) is the primary source of ATP production in PT cells, but in the setting of injury cells undergo metabolic reprograming, with reduced FAO and limited compensation by anerobic glycolysis. This proposal will address a current gap in the field by investigating the mechanisms mediating transcriptional regulation of FA utilization in the PT cells post-DNA damage. Therefore, the studies we propose are highly significant and clinically relevant to the Department of Veterans Affairs.

PI_NAMEs: MALLIPATTU, SANDEEP K (contact)

PROJECT_TERMS: Acetyl Coenzyme A;Acute Renal Failure with Renal Papillary Necrosis;Agonist;American;Anabolism;Aristolochic Acids;Attenuated;Binding Sites;Cardiovascular Diseases;cardiovascular risk factor;Cell Cycle Arrest;cell dedifferentiation;Cell Differentiation process;cell injury;Cell Physiology;Cells;chemotherapeutic agent;ChIP-seq;Chronic Kidney Failure;Cisplatin;Clinical;clinically relevant;Compensation;Data;Diglycerides;DNA Damage;DNA Repair;Down-Regulation;extracellular;Fatty Acids;Fibroblasts;Funding;General Population;Generations;Genes;Glycolysis;Goals;Human;in silico;inducible gene expression;Injury;Injury to Kidney;interest;Ischemia;Kidney;kidney biopsy;knock-down;Lipids;macromolecule;Mediating;Metabolic;Metabolic Pathway;Metabolism;Mitochondria;mouse model;Mus;Myofibroblast;Nonesterified Fatty Acids;novel;novel therapeutic intervention;Organoids;overexpression;oxidation;Oxidative Stress;Palmitates;Pathway interactions;peroxidation;Phase;PPAR alpha;Pre-Clinical Model;Predisposition;Prevalence;prevent;Production;Profibrotic signal;Proliferating;Reactive Oxygen Species;Recovery;Regression Analysis;Regulation;Renal glomerular disease;repaired;Research;Respiration;Risk Factors;Role;Secondary to;Signal Transduction;Signaling Molecule;single nucleus RNA-sequencing;Source;Testing;Therapeutic;Toxin;transcription factor;Transcriptional Regulation;transcriptome sequencing;Triglycerides;United States Department of Veterans Affairs;Veterans

PROJECT_TITLE: Role of KLF15 in proximal tubule metabolism


ORG_CITY: OKLAHOMA CITY

ORG_NAME: OKLAHOMA CITY VA MEDICAL CENTER

ORG_STATE: OK

PHR: Project Narrative Osteoarthritis (OA) is a leading cause of chronic pain and disability in our Veterans who develop OA at significantly younger ages and in higher numbers than non-Veterans. There are no disease modifying anti- osteoarthritis drugs (DMOAD) or treatments. This proposal will determine if vagal nerve stimulation delivered for 10 minutes a day will improve pain or prevent progression in two preclinical models of post-traumatic OA.

PI_NAMEs: HUMPHREY, MARY BETH (contact)

PROJECT_TERMS: Acetylcholine;Acute;Acute Pain;Address;Age;alpha-bungarotoxin receptor;Animal Model;Ankylosing spondylitis;Anti-Inflammatory Agents;Antiinflammatory Effect;Arthralgia;Automobile Driving;bench to bedside;Biological Markers;biomarker identification;bone;Bone Marrow;Bone Spur;burden of illness;Cartilage;Cells;Choline O-Acetyltransferase;cholinergic;Cholinergic Fibers;Chondrocytes;Chronic;Chronic disability;chronic pain;Clinical;Clinical Data;Clinical Trials;cohort;cytokine;Cytometry;Data;Degenerative polyarthritis;Development;Disease;Disease Pathway;Early treatment;Environment;Epilepsy;FDA approved;fibromyalgia pain;Gene Expression;Goals;Hand;Health;Healthcare Systems;Heterogeneity;Histologic;Human;Image;Immune;Immunophenotyping;improved;Inflammation;Inflammatory;inhibitor;joint injury;joint loading;Joints;Macrophage;mast cell;Measures;Mechanics;Medial meniscus structure;Mediating;Mediator;meniscus injury;Meniscus structure of joint;Mental Depression;methyllycaconitine;microCT;Modeling;Molecular;Molecular Disease;mouse model;multidisciplinary;Mus;Nerve;Nerve Growth Factors;Neuroglia;Neurons;Neurotrophic Tyrosine Kinase Receptor Type 1;new therapeutic target;NGFR Protein;Nociception;novel therapeutic intervention;Operative Surgical Procedures;osteoarthritis pain;Outcome;Pain;pain reduction;Parasympathetic Nervous System;Pathogenesis;Pathology;Pathway interactions;Patient Selection;patient subsets;Periosteum;Peripheral Blood Mononuclear Cell;Pharmaceutical Preparations;Phenotype;Pilot Projects;pre-clinical;Pre-Clinical Model;predictive marker;prevent;primary endpoint;Production;programs;protein expression;Proteins;Psoriatic Arthritis;radiological imaging;Reporter;Research;response;Rheumatoid Arthritis;Sampling;secondary endpoint;Serum;Signal Transduction;Spleen;spontaneous pain;Stem Cell Factor;Stratification;substantia spongiosa;Synovial joint;Synovial Membrane;Synovitis;System;systemic inflammatory response;T-Lymphocyte;targeted treatment;Testing;Time;Traumatic Arthropathy;Treatment Efficacy;Veterans;Weight-Bearing state;Work

PROJECT_TITLE: BCCMA:  Targeting Osteoarthritis Pain and Progression: Preclinical OA models of vagal nerve stimulation to reduce pain and progression of OA


PHR: Several human neurodegenerative conditions are associated with abnormal protein depositions in brain neurons leading to cell death. Searching for suppressors of proteotoxicity, we have identified mitochondrial energetic metabolism and the NAD+ biosynthetic salvage pathway as excellent targets. The goal of this application is to test the unconventional hypothesis that four NAD+ biosynthetic enzymes possess additional functions as cytoprotective chaperones in the context of proteotoxic stress in human neurons. We believe the proposed studies are germane to the important mission of the VA. Understanding the fundamental mechanisms that offer protection against proteotoxicity is crucial for comprehending the etiology of age-related neurodegenerative diseases, prevalent in the Veterans and their families, and a prerequisite to devise therapeutic interventions aiming to neuroprotection, the ultimate goal of our project.

PI_NAMEs: BARRIENTOS, ANTONI  (contact)

PROJECT_TERMS: Acceleration;Address;Age;age related;age related decline;age related neurodegeneration;age-related disease;Aging;alpha synuclein;Autophagocytosis;Binding;Bioenergetics;Biogenesis;Biosynthetic Proteins;Brain;Cell Death;Cells;Cessation of life;cognitive performance;Complex;Cytoprotection;Data;Deposition;Deterioration;Disease;Disease Outcome;Disease Progression;efficacy study;enzyme pathway;Enzymes;Etiology;Family;Fibroblasts;fly;General Population;Genetic;Glutamate-ammonia-ligase adenylyltransferase;Goals;Grant;hallmarks of aging;healthspan;Housekeeping;Human;Huntington Disease;Huntington gene;in vivo;induced pluripotent stem cell;interdisciplinary approach;Length;Maintenance;Metabolic;Metabolism;misfolded protein;Mission;Mitochondria;Modeling;Molecular;Molecular Chaperones;Molecular Target;mouse model;Nerve Degeneration;neuron loss;Neurons;neuroprotection;Niacinamide;Nicotinamidase;nicotinamide phosphoribosyltransferase;nicotinamide-beta-riboside;nicotinate;nicotinate mononucleotide;Nicotinic Acids;novel;novel therapeutic intervention;overexpression;Parkinson Disease;Pathway interactions;patient derived induced pluripotent stem cells;Patients;Physical Performance;pluripotent stem cell differentiation;polyglutamine;postmitotic;preclinical efficacy;prevent;protein misfolding;Proteins;proteostasis;proteotoxicity;recruit;Reporting;Research;resistance mechanism;Role;Sirtuins;Stimulation of Cell Proliferation;Stress;Structure;Structure-Activity Relationship;synucleinopathy;System;Testing;Therapeutic Intervention;tool;Toxic effect;Translations;United States Department of Veterans Affairs;Veterans;Yeast Model System;yeast protein;Yeasts

PROJECT_TITLE: Slowing proteotoxic neurodegeneration by boosting mitochondrial bioenergetics and recruiting a novel class of chaperones


PHR: PROJECT NARRATIVE  Traumatic brain injury (TBI) is a major problem in the veteran population and no treatments have yet been proven to improve long-term recovery. The object of this application is to test our hypothesis that endothelium- targeted deletion of the miR-15a/16-1 cluster attenuates BBB disruption and subsequent pathological cascades after TBI, thereby contributing to increased BBB stabilization, reduced neuronal/white matter loss, and improved long-term neurological outcomes in traumatic brain injury. The successful implementation of this proposal will eventually lead us to develop novel microRNA-based drugs for the effective treatment of traumatic brain injury.

PI_NAMEs: YIN, KEJIE  (contact)

PROJECT_TERMS: American;Attenuated;Binding;Biological Markers;Biological Process;Blood - brain barrier anatomy;Blood brain barrier dysfunction;Blood Vessels;blood-brain barrier disruption;Brain;brain endothelial cell;Brain Injuries;carcinogenesis;Cardiovascular system;Cells;cerebral microvasculature;cerebrovascular;Cerebrovascular system;Cerebrum;clinical diagnosis;clinical prognosis;Cognitive deficits;Dose;Edema;effective therapy;Endothelial Cells;Endothelium;European;Event;Extravasation;Functional disorder;Genetic;Hemorrhage;Human;Human Resources;Immune;immune cell infiltrate;Impairment;improved;Individual;Inflammation;Inflammatory Response;inhibitor;Injury;Intravenous;Ischemic Brain Injury;long term recovery;Mediating;Medical;microRNA delivery;MicroRNAs;migration;military veteran;Molecular;Mus;Myocardial Infarction;Myocardial Ischemia;Nervous System Disorder;Nervous System Trauma;neurobehavioral;Neurologic Deficit;Neurological outcome;neuron loss;Neurons;novel;Outcome;Pathogenesis;Pathologic;Peripheral;Permeability;Pharmaceutical Preparations;Pharmacologic Substance;Pharmacotherapy;Plasma;Play;post-trauma;posttranscriptional;prevent;protein expression;Proteins;Regulation;Rodent;Role;Secondary to;Services;TBI treatment;Testing;therapeutically effective;Tight Junctions;Time;Translations;Traumatic Brain Injury;Untranslated Regions;Untranslated RNA;Veterans;white matter;white matter injury

PROJECT_TITLE: Regulatory microRNAs-mediated cerebrovascular protection and traumatic braininjury


ORG_CITY: DALLAS

ORG_NAME: VA NORTH TEXAS HEALTH CARE SYSTEM

PHR: PROJECT NARRATIVE Melanoma is an important cause of morbidity and mortality in the U.S. and among military veterans. Immune treatments have prolonged survival of many patients with metastatic melanoma, but resistance to this modality remains high. We discovered: (1) novel pathway (DC-HIL/SD4) that suppresses T-cell immunity; (2) soluble form of DC- HIL that binds to syndecan-4 (SD4) on endothelial cells leading to angiogenesis while inhibiting extravasation of T cells; and (3) precise DC-HIL ligand in SD-4 that is a rare highly-sulfated 8-oligosaccharide (rHS), whose infusion into melanoma-bearing mice reduced tumor growth and expression of angiogenic factors within the tumor. Our proposal will: delineate consequences of DC-HIL and rHS interaction on immunosuppression vs. angiogenesis in melanoma; develop rHS-targeted treatment for melanoma; and characterize expression of rHS during melanoma progression and metastasis.

PI_NAMEs: CRUZ, PONCIANO D (contact)

PROJECT_TERMS: Ablation;angiogenesis;Angiogenesis Pathway;Angiogenic Factor;anti-PD-L1;anti-PD-L1 therapy;B-Lymphocytes;Binding;Biological Assay;Blood Vessels;Carbohydrates;Cells;chemokine;Cre lox recombination system;CTLA4 gene;effective therapy;Endothelial Cells;Epitopes;Extravasation;FGF2 gene;Fibroblasts;Genes;Growth;Heparan Sulfate Biosynthesis;Heparan Sulfate Proteoglycan;Heparitin Sulfate;Histology;Human;Immune;immune checkpoint;Immune checkpoint inhibitor;Immunity;Immunoprecipitation;Immunosuppression;Impairment;Implant;improved;in vivo;Infusion procedures;Leucocytic infiltrate;Ligands;Link;Location;Malignant Neoplasms;Mediating;Melanoma;Melanoma Cell;Melanoma patient;Metastatic Melanoma;Metastatic Neoplasm to the Lung;military veteran;Modality;Modeling;Monoclonal Antibodies;Morbidity - disease rate;mortality;mouse model;Mus;Mutation;Neoplasm Metastasis;novel;Oligosaccharides;Oranges;Outcome;Pathogenesis;Pathway interactions;Patients;Pattern;Polysaccharides;programmed cell death ligand 1;Property;Proteoglycan;receptor;Resistance;Signal Transduction;Skin;subcutaneous;Sulfate;syndecan-4;T cell response;T Chain;T-Lymphocyte;Tamoxifen;targeted treatment;Testing;Tissues;tumor;Tumor Angiogenesis;tumor growth;tumor progression;Tyrosine Kinase Inhibitor;Vascular Endothelial Growth Factors;Xenograft procedure

PROJECT_TITLE: DC-HIL in cancer


PHR: Project Narrative Lung cancer is a devastating disease that disproportionally affects veterans due to chemical exposure during the war and high smoking rate. Lung squamous carcinoma (LUSC) is particularly difficult to treat as there are no personalized cancer medicines available currently. We, and others, have discovered that a complex of molecules, called mTORC2, are hyperactive in the above subtypes of lung cancer, representing a novel therapeutic target. Our overall goal of this project is (1) to gain a rigorous understanding of the contribution of mTORC2 to LUSC, and (2) to further investigate if targeting mLST8 or RICTOR, two critical components of the mTORC2, can be used to selectively inhibit mTORC2 and enhance antitumor immunity for treatment of LUSC.

PI_NAMEs: CHEN, JIN  (contact)

PROJECT_TERMS: Affect;Age;anti-PD-1;anti-tumor immune response;antiviral immunity;Blood Vessels;Cancer Etiology;Cause of Death;cell motility;Cell Physiology;Cell surface;Cells;Cessation of life;checkpoint receptors;checkpoint therapy;Chemical Exposure;chemotherapy;Clinical;Complex;Coupled;COVID-19 vaccine;CTLA4 gene;Data;Data Set;Disease;Dose;driver mutation;effector T cell;Endothelium;Environment;Feedback;Genetic;Goals;Hyperactivity;Immune;immune checkpoint;immune checkpoint blockade;Immune checkpoint inhibitor;Immunofluorescence Immunologic;immunomodulatory therapies;Immunotherapy;improved;In Situ;in vivo;Individual;Infiltration;inhibitor;interstitial;Lewis Lung Carcinoma;Ligands;loss of function;Lung Adenocarcinoma;Macrophage;Malignant neoplasm of lung;Malignant Neoplasms;Mediator;Medicine;Military Personnel;military veteran;Molecular;molecular targeted therapies;Mutation;nanoparticle;neoplastic cell;new therapeutic target;novel therapeutic intervention;Nutrient;Oncogenic;P-selectin ligand protein;Pathway interactions;Patients;pharmacologic;Phase II Clinical Trials;Phosphotransferases;PIK3CA gene;PIK3CG gene;Pinocytosis;Play;Positioning Attribute;Production;programmed cell death ligand 1;programmed cell death protein 1;Proto-Oncogene Proteins c-akt;PTEN gene;recruit;Refractory;Research;Resistance;response;Role;Services;Signal Transduction;Smoking;Squamous cell carcinoma;Squamous Cell Lung Carcinoma;Stress;success;T cell infiltration;T-Lymphocyte;targeted treatment;Testing;The Cancer Genome Atlas;translational potential;treatment strategy;tumor;tumor growth;Tumor Immunity;tumor metabolism;tumor-immune system interactions;Tumor-Infiltrating Lymphocytes;Vascular Endothelial Cell;Vascular Endothelium;Veterans;Visualization;War

PROJECT_TITLE: Targeting mTORC2 in lung squamous cancer


ADMINISTERING_IC: MH

IC_NAME: NATIONAL INSTITUTE OF MENTAL HEALTH

NIH_SPENDING_CATS: Biotechnology;Brain Disorders;Epilepsy;Gene Therapy;Genetics;Mental Health;Neurodegenerative;Neurosciences

ORG_CITY: SEATTLE

ORG_NAME: ALLEN INSTITUTE

ORG_STATE: WA

PHR: PROJECT NARRATIVE The human brain is composed of a remarkable diversity of cell types and classes, and at present, we have limited knowledge about the distinct contributions of each cell type and class to normal brain function. Furthermore, brain disorders are generally regarded as the consequence of cell type and circuit dysfunction, but the dearth of well-validated molecular genetic tools available to directly explore this relationship in large primate brains has constrained progress, especially for translational research. Our proposal aims to remedy this by engineering novel AAV capsids to allow enhanced neuronal transduction of primate brain, developing a suite of optimized AAV vectors for more precise cell type and cell class-selective delivery of transgenes, and testing if virus-mediated restoration of sodium channel function in forebrain inhibitory neurons can correct the devastating neurological deficits of Dravet syndrome.

PI_NAMEs: KALUME, FRANCK K;LEIN, ED ;LEVI, BOAZ PIRIE;TING, JONATHAN T (contact)

PROGRAM_OFFICER_NAME: KIM, DOUGLAS SUN-IL

PROJECT_TERMS: adeno-associated viral vector;Adult;Biodistribution;Brain;brain cell;brain circuitry;Brain Diseases;BRAIN initiative;brain tissue;Capsid;Categories;cell type;Cells;cellular transduction;Cerebrospinal Fluid;childhood epilepsy;Clinical;Consumption;cost;Dependovirus;discrimination task;Disease;Dose;dravet syndrome;Engineering;Enhancers;Epilepsy;Etiology;experimental study;Functional disorder;Gene Delivery;Gene Expression;gene replacement therapy;gene therapy;Genetic;Human;improved;in vivo;Individual;inhibitory neuron;Injections;Intravenous;Knowledge;Lead;Mediating;Methods;Molecular;Molecular Genetics;Molecular Profiling;mouse genetics;mouse model;Mus;Neocortex;neocortical;Neurologic Deficit;Neurons;nonhuman primate;novel;Phenotype;Physiology;Positioning Attribute;Primates;Process;Prosencephalon;recombinase;Reporter;Resolution;restoration;Role;Route;Safety;screening;selective expression;Shapes;Site;Slice;Sodium Channel;targeted treatment;Taxonomy;Testing;therapeutic gene;Therapeutic Intervention;therapeutic transgene;Time;Tissues;tool;transcriptomics;transduction efficiency;Transduction Gene;transgene delivery;transgene expression;Transgenes;Transgenic Organisms;Translating;Translational Research;Validation;vector;Viral;Viral Vector;Virus;virus testing;Visual Cortex;visual discrimination;voltage

PROJECT_TITLE: Cell type selective viral tools to interrogate and correct non-human primate and human brain circuitry


ORG_CITY: SAN ANTONIO

ORG_NAME: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM

PHR: Cancer is one of the top threats to the health of veterans. Recently developed tumor immunotherapies, including tumor vaccines have greatly improved the survival of cancer patients. However, only a small percentage of treated cancer patients experience long-lasting benefits from current tumor immunotherapies partially due to the lack of knowledge how our immune system responds to these therapies. Our project is focused on a subset of tumor-targeting immune cells, namely tumor-specific stem-like CD8 T lymphocytes. These immune cells have been established as the key to mediate the response of tumor vaccine. Based on our recent findings that these immune cells bear a unique migration pattern, we will test whether we can specifically targeting these immune cells to boost the efficacy of tumor vaccine as well as local irradiation- released endogenous tumor antigen.

PI_NAMEs: ZHANG, NU  (contact)

PROJECT_TERMS: acute infection;Adjuvant;Adopted;Affinity;Antigens;Area;Aryl Hydrocarbon Receptor;Biology;Cancer Patient;cancer survival;cancer vaccination;Cancer Vaccines;CD8-Positive T-Lymphocytes;cell motility;Cells;Communication;Defect;design;Development;draining lymph node;drug candidate;Exhibits;experience;experimental study;Future;Genetic;Genetic Transcription;Harvest;Health;Healthcare Systems;Immune;immune checkpoint blockade;Immune response;Immune system;Immune Targeting;Immunotherapy;improved;improved outcome;inhibitor;insight;Investigation;irradiation;Knowledge;Lymph Node Tissue;Lymphoid;Lymphoid Tissue;Malignant Neoplasms;Mediating;migration;Modeling;Molecular;Molecular Target;Mus;Names;neoplasm immunotherapy;novel therapeutic intervention;pathogen;Patients;Pattern;PD-1/PD-L1;PD-L1 blockade;pharmacologic;Phenotype;Population;prevent;progenitor;programs;rational design;receptor;Research;Residencies;response;Role;Signal Transduction;Site;stem;stem cell biology;stem cell differentiation;stem cells;stemness;synergism;System;T cell differentiation;T cell response;T memory cell;T-Lymphocyte;T-Lymphocyte Subsets;Testing;tissue resident memory T cell;Tissues;transcription factor;Transforming Growth Factors;Translating;translational potential;tumor;Tumor Antigens;Tumor Immunity;Veterans

PROJECT_TITLE: Targeting lymphoid tissue residency to boost tumor immunotherapies


ORG_CITY: LOS ANGELES

ORG_NAME: VA GREATER LOS ANGELES HEALTHCARE SYSTEM

ORG_STATE: CA

PHR: Lung cancer is the leading cause of cancer death among US Veterans despite recent advances in therapy. The National Lung Screening Trial has successfully demonstrated the efficacy of lung cancer screening in reducing lung cancer mortality. Lung cancer screening programs at VA medical centers are being implemented. We anticipate an increase in the rate of early-stage diagnoses. This research will develop a systematic approach to identify and integrate signatures from genetic, tumor microenvironment, and clinical computed tomography images to distinguish between aggressive and indolent early-stage lung cancer. The study will utilize the National Lung Screening Trial data and validate signatures from publicly available data sets. Predicting tumor behavior will improve personalized patient therapy for lung cancer.

PI_NAMEs: TRAN, LINH M (contact)

PROJECT_TERMS: Aggressive behavior;Atlases;Behavior;behavioral study;Biological;Cancer Etiology;Cell Lineage;cell type;Cells;Cessation of life;Characteristics;Clinical;clinical imaging;Clinical Management;cohort;Data;Data Set;Diagnosis;Disease;Early treatment;Exhibits;exome sequencing;follow-up;Genetic;genetic signature;genomic profiles;genomic signature;Genomics;Goals;Heterogeneity;Image;Immune response;Immunofluorescence Immunologic;Immunotherapy;improved;Indolent;low dose computed tomography;Lung;Lung Adenocarcinoma;lung cancer screening;Machine Learning;Malignant neoplasm of lung;Malignant Neoplasms;Medical center;Molecular;Molecular Profiling;Morphology;mortality;Mutation;Nodule;Non-Small-Cell Lung Carcinoma;Outcome;patient prognosis;Patients;Population;predictive modeling;Radiogenomics;radiomics;Research;Resected;Resistance;screening;screening program;Semantics;Shapes;Somatic Mutation;Subjects Selections;targeted treatment;Techniques;The Cancer Genome Atlas;Therapeutic;Therapeutic Equivalency;Time;transcriptome;tumor;tumor behavior;tumor microenvironment;Veterans;X-Ray Computed Tomography

PROJECT_TITLE: The Pulmonary Pre-malignancy Atlas in the Lung Adenocarcinoma Spectrum


ORG_CITY: SAN DIEGO

ORG_NAME: VA SAN DIEGO HEALTHCARE SYSTEM

PHR: 8. Project Narrative The inflammatory bowel diseases (IBD) affect over 50,000 Veterans in the United States, cause significant morbidity and pose a significant financial burden to our VA healthcare system. Here, we use unique chronic mouse models of IBD and B cell function to investigate the role of beta7 integrins (targeted by FDA-approved drugs, e.g. vedolizumab) on B cell migration, localization, IgA production and control of the microbiota during experimental IBD. We believe that achieving an understanding of the cells and molecules that exert control over the microbiota might directly translate to human IBD and lead to the discovery of new ways to treat or even prevent IBD in genetically-susceptible individuals.

PI_NAMEs: RIVERA-NIEVES, JESUS  (contact)

PROJECT_TERMS: Acceleration;Address;Affect;Antibodies;B-Lymphocytes;Bacteria;Bacterial Antigens;CD19 gene;cell motility;Cell Physiology;Cells;cellular targeting;Cholera Vaccine;Chronic;Circulation;Clinical;Colitis;Crohn's disease;cytokine;Cytometry;Data;Defense Mechanisms;Defensins;Dendritic Cells;Dependence;disease model;Disease Progression;Docking;Dose;drug action;dysbiosis;early onset;Elements;Epithelium;Exhibits;experience;FDA approved;fecal transplantation;Feces;Financial Hardship;Growth;gut microbiota;Healthcare Systems;healthy volunteer;Home;Homeostasis;Homing;Human;IgA Deficiency;Ileitis;Immune response;Immune Tolerance;Immunity;Immunization;Immunoglobulin A;Immunoglobulin-Secreting Cells;Immunoglobulins;Immunologist;Immunology;Impairment;Individual;Inflammatory Bowel Diseases;Integrins;Interleukin-10;Intervention;Intestines;Investigation;Lamina Propria;Lead;Ligands;Lymphocyte;Maintenance;Mediating;microbiota;microbiota composition;migration;Modeling;Molecular;Monoclonal Antibodies;Morbidity - disease rate;mouse model;mucosal addressin cell adhesion molecule-1;Mucosal Immunity;Mucous Membrane;Mus;mutant;Mutant Strains Mice;natalizumab;novel;Oral;pathobiont;Pathogenicity;Patients;Peer Review;Pharmaceutical Preparations;Phenotype;Plasma Cells;Play;Predisposition;prevent;Process;Production;Proliferating;Publishing;receptor;recruit;Regulation;Regulatory T-Lymphocyte;Reporting;response;Ribosomal RNA;Role;Secretory Immunoglobulin A;Severities;Siblings;Surface;T-Lymphocyte;Testing;Therapeutic;Tissues;TNF gene;transcytosis;Translating;treatment strategy;Tretinoin;United States;Veterans;Work;YY1 Transcription Factor

PROJECT_TITLE: Control by Beta 7 integrins of the bacterial triggers of IBD


ORG_STATE: TX

PHR: The incidence of chronic kidney disease is increasing as our population ages and in correlation with rising obesity rates. The VA population has a higher prevalence of diabetic kidney disease than the general population, much of it as a complication of obesity. We recently found that insulin levels may contribute to tubular injury in the kidney during obesity. Our proposal seeks to understand the role of a critical protein in the kidney, AMPK, in mediating the effect of insulin and whether insulin regulates AMPK via effect on an enzyme that regulates hydrogen sulfide production. The insights gained from these studies will have a major impact on our understanding of obesity in progressive kidney disease.

PI_NAMEs: SHARMA, KUMAR  (contact)

PROJECT_TERMS: 6-phosphogluconate;Adipose tissue;Affect;Age;Biological Markers;Blood;Blood Glucose;Catalytic Domain;cell injury;Cells;Chronic Kidney Failure;circulating biomarkers;Complication;Complications of Diabetes Mellitus;Cystathionine;Data;Diabetes Mellitus;diabetic;Diabetic Nephropathy;Disease Progression;Enzymes;Exposure to;Fatty acid glycerol esters;General Population;Generations;HDAC6 gene;Heart;High Fat Diet;High Prevalence;Histology;Hydrogen Sulfide;Hypertension;IGA Glomerulonephritis;in vivo;Incidence;Inflammatory;inhibitor;Injury;Injury to Kidney;insight;Insulin;Insulin Receptor;Insulin Resistance;insulin sensitivity;insulin signaling;Kidney;Kidney Diseases;knock-down;Knock-out;Knockout Mice;Lipids;Liver;Lyase;Mediating;Mediator;metabolomics;Methods;Modeling;Mus;Muscle;non-diabetic;Non-Insulin-Dependent Diabetes Mellitus;novel;Obesity;Obesity associated kidney disease;Organ;Outcome;Pathway interactions;Patients;Play;podocyte;Population;Production;protective effect;Proteins;Publishing;Receptor Inhibition;Regulation;Renal Hypertension;restoration;Role;sensor;Signal Transduction;Techniques;Testing;theories;Therapeutic;Tissues;Toxic effect;Tubular formation;Urine

PROJECT_TITLE: New Insights in Mechanisms of Renal Injury


PHR: Hospitalization for HF is the 2nd most common cause of cardiovascular hospitalization among Veterans. Patients who are hospitalized for HF often have significant deficits in strength, mobility and balance that can lead to inability to maintain functional independence. Veterans hospitalized for HF often have a high treatment workload, which leads to difficulty coping with stressors and [limits their motivation to participate in physical rehabilitation. Therefore, helping Veterans to expand their capacity to cope is important.] The COACH-HF intervention pairs Capacity Coaching with physical rehabilitation to augment Veterans’ capacity to cope with their high treatment workload - including the rehabilitation intervention. This research will [modify the proposed COACH-HF intervention] with stakeholder engagement, then evaluate feasibility, acceptability, [and improvement in rehabilitation adherence from Capacity Coaching] in a pilot study of 25 Veterans. This knowledge will be applied to a finalized COACH-HF protocol that will be tested in a larger study.

PI_NAMEs: FLINT, KELSEY M (contact)

PROJECT_TERMS: acceptability and feasibility;Address;Adherence;Aerobic;Aerobic Exercise;Age;Appointment;Area;arm;Award;Behavior Therapy;Cardiac rehabilitation;Cardiovascular system;career;career development;Caregivers;Categories;Chronic Disease;Clinical;Clinical Research;Clinical Trials Design;Colorado;comorbidity;coping;Decision Making;design;Dose;efficacy testing;Enrollment;Environment;Equilibrium;Exercise;experience;Feedback;Feeling;Focus Groups;Foundations;functional independence;Funding;Genetic Transcription;Goals;Health;Health behavior change;Health Personnel;Heart failure;Home;Hospitalization;improved;innovation;insight;interest;Intervention;Interview;Knowledge;lens;Literature;Measures;Medical;Medical center;member;Methods;Modification;Motivation;novel;novel strategies;older adult;Outcome;Participant;Patients;peer support;Pharmaceutical Preparations;Physical Function;Physical Rehabilitation;physical therapist;Physical therapy;Pilot Projects;pilot test;post intervention;Principal Investigator;programs;Protocols documentation;Qualitative Research;Randomized;Rehabilitation therapy;rehabilitative care;Reporting;Research;Research Personnel;Resources;skeletal muscle weakness;skills;Specialist;standard of care;stressor;Structure;Surveys;Techniques;tertiary care;Testing;therapy design;Training;treatment arm;Universities;Veterans;Wellness coaching;Workload;Writing

PROJECT_TITLE: Modification and Pilot Testing of The Capacity cOaching And exerCise after Hospitalization for Heart Failure (COACH-HF) Intervention

STUDY_SECTION_NAME: Career Development Program - Panel II[RRD9]


ORG_NAME: VA PUGET SOUND HEALTHCARE SYSTEM

PHR: Alzheimer’s disease, the most frequent aging-associated dementia, predominantly affects individuals age 65 or older. After age 65, the likelihood of developing Alzheimer’s disease doubles every 5 years. Approximately half of American Veterans are age 65 years or older, making them vulnerable to developing Alzheimer’s disease. Further, head injuries, including traumatic brain injuries experienced by Veterans during their military service, puts individuals at elevated risk of dementia. The burden placed on American Veterans afflicted by Alzheimer’s disease is incalculable, as the disease causes progressive memory loss that erodes their independence and ultimately leads to death. Here we propose to use models to examine functional and molecular aspects of brain changes that occur in Alzheimer’s disease and to identify new neuroprotective strategies. This may lead to potential therapeutic interventions for the benefit of all those affected by Alzheimer’s disease including Veterans.

PI_NAMEs: LIACHKO, NICOLE FARON (contact)

PROJECT_TERMS: Affect;Aging;aging related;aging related disease;Alzheimer's Disease;Alzheimer's disease patient;American;Amyloid beta-Protein;Amyotrophic Lateral Sclerosis;Animals;Behavioral;Biological Assay;Biology;Brain;Brain region;Caenorhabditis elegans;Cells;cerebral atrophy;Cessation of life;Code;comorbidity;Craniocerebral Trauma;Data;Dementia;dementia risk;Disease;Disease Progression;Exhibits;experience;Foundations;frontotemporal lobar dementia amyotrophic lateral sclerosis;Functional disorder;Future;gain of function;Gene Expression;Genes;hippocampal sclerosis;Human;human old age (65+);Immunohistochemistry;Impaired cognition;in vivo;Individual;Inherited;insight;Link;Maps;Mediating;Memory Loss;military service;Modeling;Modification;Molecular;mouse model;Mus;Mutation;Nature;Nerve Degeneration;Nervous System Disorder;Neurodegenerative Disorders;Neurofibrillary Tangles;neuroimaging;neuroinflammation;Neuronal Dysfunction;Neurons;neuroprotection;neurotoxic;neurotoxicity;new therapeutic target;Outcome;Pathologic;Pathology;Patients;Persons;Population;Process;protein aggregation;Protein Dynamics;Protein Isoforms;protein TDP-43;Proteins;response;RNA Splicing;Role;Senile Plaques;Stress;synergism;tau aggregation;tau Proteins;TDP-43 aggregation;Tertiary Protein Structure;therapeutic development;Therapeutic Intervention;Time;Toxic effect;transcriptomics;Transgenic Mice;Traumatic Brain Injury;Veterans;Work

PROJECT_TITLE: Mechanisms of TDP-43 neurotoxicity in Alzheimer's disease