FUNDING_MECHANISM: OTHER RESEARCH-RELATED

NIH_SPENDING_CATS: Biotechnology;Cancer;Cancer Genomics;Clinical Research;Genetics;Human Genome;Immunotherapy;Lung;Lung Cancer;Machine Learning and Artificial Intelligence;Networking and Information Technology R&D (NITRD);Prevention;Skin Cancer

ORG_CITY: NEW YORK

ORG_NAME: SLOAN-KETTERING INST CAN RESEARCH

ORG_STATE: NY

PHR: PROJECT NARRATIVE Conventional deep targeted sequencing approaches to liquid biopsy for circulating tumor DNA (ctDNA) face fundamental sensitivity barriers in low volume disease, which largely restricts use of liquid biopsy to advanced malignancy. Recently, we demonstrated that use of whole genome sequencing (WGS) of plasma can overcome prevailing sensitivity barriers in liquid biopsy through use of advanced error suppression and matched tumor tissue, allowing for detection of postoperative minimal residual disease (MRD) that was linked to early cancer recurrence in non-small cell lung cancer and colorectal cancer. In this proposal, I seek to use advanced machine learning to overcome matched tumor tissue dependency and vastly expand the applicability of our WGS-based approach, which will enable ultrasensitive therapeutic monitoring of response to immunotherapy and detection of postoperative MRD with plasma WGS alone.

PI_NAMEs: WIDMAN, ADAM  (contact)

PROGRAM_OFFICER_NAME: BIAN, YANSONG

PROJECT_TERMS: Adjuvant Therapy;Aftercare;Artificial Intelligence;Award;Biological Markers;burden of illness;cancer genomics;cancer recurrence;cancer type;career;career development;cell free DNA;Cells;checkpoint inhibition;Chromatin;Clinical;Clinical Trials;cohort;Collection;Colorectal Cancer;Communities;Complement;Complex;cost;Data;deep learning;Dependence;Detection;Development Plans;Disease;Disease-Free Survival;Dose;Early Diagnosis;Early identification;empowerment;Environment;Epigenetic Process;Face;falls;Genome;genome sequencing;Genomics;Goals;Image;Immunotherapy;improved;Infusion procedures;innovation;Institution;instructor;International;laboratory experience;learning classifier;Length;Link;liquid biopsy;Machine Learning;Malignant - descriptor;Malignant neoplasm of lung;Malignant Neoplasms;Measures;Medicine;Melanoma;Memorial Sloan-Kettering Cancer Center;Mentors;Mentorship;Metastatic Melanoma;Methods;Monitor;Mutagenesis;Mutation;Nature;Neoadjuvant Therapy;New York;next generation sequencing;Noise;non-invasive monitor;Non-Small-Cell Lung Carcinoma;Nucleosomes;Outcome;Patient Care;Patients;Physicians;Plasma;Positioning Attribute;Postoperative Period;Precision therapeutics;predictive modeling;prognostic;Protocols documentation;prototype;radiological imaging;Recurrent disease;Regimen;Relapse;Research;Residual Neoplasm;Resistance;response;Sampling;Scientist;Screening for cancer;Signal Transduction;Single Nucleotide Polymorphism;Site;skills;Solid Neoplasm;Source;Syncope;targeted sequencing;tenure track;Therapeutic;Tobacco;Toxic effect;Training;treatment response;tumor;Tumor Burden;tumor DNA;Tumor Tissue;unnecessary treatment;Update;Validation;variant detection;Vision;Visit;whole genome

PROJECT_TITLE: Advanced machine learning to empower ultra-sensitive liquid biopsy in melanoma and non-small cell lung cancer

STUDY_SECTION: NCI

STUDY_SECTION_NAME: Career Development Study Section (J)[NCI-J]


ADMINISTERING_IC: NS

ARRA_FUNDED: N

ED_INST_TYPE: SCHOOLS OF PHARMACY

FUNDING_MECHANISM: TRAINING, INSTITUTIONAL

IC_NAME: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

ORG_CITY: SALT LAKE CITY

ORG_COUNTRY: UNITED STATES

ORG_DEPT: PHARMACOLOGY

ORG_FIPS: US

ORG_NAME: UNIVERSITY OF UTAH

ORG_STATE: UT

PHR: The objective of Training in the Development of Novel Interventions for the Treatment of Neurological and Neurobehavioral Disorders is to provide one pre-doctoral and one post-doctoral/clinical fellow per year with formal education in the translational processes needed for moving basic science discoveries to clinical practice. The program will capitalize on strong translational training opportunities already available at the University of Utah and will complement those opportunities with new programming to develop burgeoning “professional translators” poised to promote the translation of basic research findings to improved therapeutic outcomes in patients.

PI_NAMEs: KEEFE, KRISTEN A (contact)

PROGRAM_OFFICER_NAME: REZAIZADEH, KAVON PAUL

PROJECT_TERMS: Development;Intervention;Nervous System Disorder;neurobehavioral disorder;novel;Training


ADMINISTERING_IC: GM

FUNDING_MECHANISM: RESEARCH CENTERS

IC_NAME: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

NIH_SPENDING_CATS: Building Research Capacity at Institutions with Limited NIH Funding;Infectious Diseases;Lung

ORG_CITY: STILLWATER

ORG_NAME: OKLAHOMA STATE UNIVERSITY STILLWATER

ORG_STATE: OK

PI_NAMEs: CHANNAPPANAVAR, RUDRAGOUDA  (contact)

PROJECT_TERMS: Anatomy;Animals;Area;assay development;Awareness;Biomedical Research;cell analyzer;Cell Separation;Cells;Centers of Research Excellence;Collaborations;Communicable Diseases;Communities;Comparative Study;Complex;Core Facility;Data;data curation;Development;Elements;experience;Extramural Activities;Fee-for-Service Plans;Fees;Flow Cytometry;Fluorescence-Activated Cell Sorting;Foundations;Funding;Goals;Grant;Growth;Histologic;Histopathology;Human Resources;Immune System Diseases;Immunoassay;Immunofluorescence Immunologic;Immunohistochemistry;Immunologics;Immunology;Immunology procedure;immunopathology;In Vitro;in vivo;Incentives;Infrastructure;Institution;instrumentation;International;Laboratories;Lesion;Oklahoma;outreach;outreach program;Pathogenesis;Pathologic;Pathology;Phase;Pilot Projects;programs;recruit;Research;Research Design;Research Personnel;Research Project Grants;Research Support;Resources;Respiratory Center;Respiratory Disease;Scientist;service programs;Services;success;symposium;System;Technology;Tissue Model;tissue processing;Tissues;Training;user-friendly;voucher

PROJECT_TITLE: Immunopathology Core


ADMINISTERING_IC: CA

ED_INST_TYPE: SCHOOLS OF MEDICINE

FUNDING_MECHANISM: NON-SBIR/STTR RPGS

IC_NAME: NATIONAL CANCER INSTITUTE

NIH_SPENDING_CATS: Behavioral and Social Science;Cancer;Clinical Research;Clinical Trials and Supportive Activities;Comparative Effectiveness Research;Cost Effectiveness Research;Dissemination and Implementation Research;Health Disparities Research;Health Disparities and Racial or Ethnic Minority Health Research;Prevention;Skin Cancer

ORG_CITY: Newark

ORG_DEPT: INTERNAL MEDICINE/MEDICINE

ORG_NAME: RUTGERS BIOMEDICAL AND HEALTH SCIENCES

ORG_STATE: NJ

PHR: PROJECT NARRATIVE Survivors of invasive cutaneous melanoma are at high risk for skin cancer recurrence and new primary cancers, and regular thorough skin self-examination (SSE) is recommended to reduce these risks. The proposed study seeks to enhance the promising initial effects of MySmartSkin, a fully automated online intervention developed by our team, on performance of thorough SSE and prepare MySmartSkin for widespread dissemination and implementation among melanoma survivors. This work will advance the science of cancer survivorship by optimizing a promising surveillance and prevention-focused intervention for an underserved group of cancer survivors and preparing for widespread dissemination and implementation.

PI_NAMEs: HECKMAN, CAROLYN ;MANNE, SHARON L (contact)

PROGRAM_OFFICER_NAME: HALL, KARA L

PROJECT_TERMS: Address;Adoption;Behavior;behavior change;Behavioral;cancer diagnosis;cancer recurrence;Cancer Science;Cancer Survivor;Cancer Survivorship;care providers;Caring;Clinical;clinical examination;Collaborations;Community Healthcare;Consent;contextual factors;cost;Cost Analysis;cost effective;cost effectiveness;Cost Effectiveness Analysis;Cutaneous Melanoma;Data;design;Detection;Diagnosis;digital intervention;Disease;Disease Progression;Dissemination and Implementation;Early Diagnosis;Early treatment;Education;effective therapy;Effectiveness;effectiveness evaluation;effectiveness/implementation design;effectiveness/implementation trial;efficacy trial;Eligibility Determination;Ensure;experience;follow-up;Future;future implementation;General Population;Goals;Guidelines;health care settings;Healthcare;high risk;Immunotherapy;implementation evaluation;implementation framework;implementation outcomes;implementation science;improved;Incidence;informant;innovation;Intervention;intervention delivery;Interview;Lesion by Stage;Maintenance;Malignant Neoplasms;Melanoma;Methods;Modeling;models and simulation;neoplasm registry;New Jersey;Newly Diagnosed;online intervention;Participant;Performance;Persons;Physicians;Population;Prevention;Process;Professional Organizations;program costs;programs;Provider;Randomized;Randomized, Controlled Trials;Recommendation;recruit;Recurrence;Recurrent disease;Research;Resources;Risk;Risk Factors;Risk Reduction;scale up;Self-Examination;Skin;Skin Cancer;social media;Survivors;Target Populations;Techniques;Testing;Theory of Change;Thinness;Time;treatment as usual;Treatment Cost;trial design;Underserved Population;United States;usability;web page;Work

PROJECT_TITLE: A digital intervention to improve skin self-examination among melanoma survivors

STUDY_SECTION: SIHH

STUDY_SECTION_NAME: Science of Implementation in Health and Healthcare Study Section[SIHH]


NIH_SPENDING_CATS: Cancer;Cancer Genomics;Genetics;Hematology;Human Genome;Lymphatic Research;Lymphoma;Radiation Oncology;Rare Diseases;Regenerative Medicine;Stem Cell Research;Stem Cell Research - Nonembryonic - Non-Human

ORG_DEPT: RADIATION-DIAGNOSTIC/ONCOLOGY

PHR: Relevance Narrative The hematopoietic system is one of the most vulnerable organs to radiation induced damage and tumorigenesis. This study focuses on the role of the BCCIP gene in modulating hematopoietic effects of radiation and the recruitment of BCCIP protein to DNA damages sites. It is highly relevant to the mitigation of bone marrow damage caused by radiation exposure.

PI_NAMEs: SHEN, ZHIYUAN  (contact)

PROGRAM_OFFICER_NAME: WITKIN, KEREN L

PROJECT_TERMS: Acceleration;Acute;Adult;Affect;Animals;BARD1 gene;Binding;Body System;Bone Marrow;Bone Marrow Cells;Bone marrow failure;BRCA2 gene;Carcinogens;Chromosomal Breaks;Chromosomal Instability;Chromosomal Stability;Chromosomes;Clonality;Competence;Development;DNA Damage;DNA Double Strand Break;DNA Repair;Environment;epigenomics;experimental study;Genes;Genome Stability;genome-wide;Genomics;Goals;Hematopoiesis;Hematopoietic;Hematopoietic stem cells;Hematopoietic System;Hypersensitivity;Impairment;in vivo;insight;Ionizing radiation;Longevity;Lymphoma;Lymphomagenesis;mature animal;Mediating;Medical;medical countermeasure;Modeling;Molecular;Mus;Natural regeneration;Nature;Normal tissue morphology;novel;Nucleotides;Organ;Pathologic;Poly Adenosine Diphosphate Ribose;Predisposition;Process;Property;Proteins;Radiation;radiation effect;Radiation exposure;Radiation induced damage;Radiation Tolerance;reconstitution;Recovery;recruit;Role;Series;Site;stem;stem cell proliferation;stem cells;Syndrome;Testing;tissue regeneration;tumor;tumor initiation;tumor progression;Tumor Promotion;tumorigenesis

PROJECT_TITLE: Molecular modulators of radiation-induced chromosome instability and hematopoietic damage

STUDY_SECTION: RTB

STUDY_SECTION_NAME: Radiation Therapeutics and Biology Study Section[RTB]


ADMINISTERING_IC: VA

FUNDING_MECHANISM: OTHERS

IC_NAME: Veterans Affairs

ORG_CITY: AUGUSTA

ORG_NAME: CHARLIE NORWOOD VA MEDICAL CENTER

ORG_STATE: GA

PHR: Project Narrative This application requests the appointment of Dr. Wendy Bollag, Research Physiologist at the Charlie Norwood VA Medical Center (CNVAMC) and Professor of Physiology at the affiliate Augusta University, to the position of Research Career Scientist. Dr. Bollag investigates signaling mechanisms that regulate cell responses in multiple systems. One such response is skin cell growth and maturation to form the outer layer of skin and another is corneal wound healing; these processes seem to be mediated by similar signaling mechanisms. This research has relevance to corneal injury, for which combat soldiers are at high risk, as well as non-melanoma skin cancer, with about 3 million new cases annually in the US, and psoriasis, a common skin disorder affecting an estimated 400,000 veterans. Another project examines the signals regulating adrenal gland production of aldosterone, a hormone involved in salt retention and blood pressure control. Excessive secretion of aldosterone results in hypertension, which affects almost 3.5 million veterans and approximately two-thirds of patients at the CNVAMC.

PI_NAMEs: BOLLAG, WENDY B (contact)

PROJECT_TERMS: Adrenal Glands;Affect;Aging;Aldosterone;Angiotensin II;anti-cancer research;Applications Grants;Appointment;aquaporin 3;Archives;Award;Back;Biology;blood pressure control;bone;Book Chapters;Book Reviews;Calpain;career;cell growth;Cell Maturation;Cell model;Cell Physiology;Cells;Circulation;colon cancer treatment;combat;community engagement;Cornea;corneal epithelial wound healing;corneal epithelium;Corneal Injury;cost;COVID-19;Department of Defense;Dermatologic;Dermatology;Differentiation and Growth;Disease;editorial;Education;Endocrinology;Epidermis;Equipment;Exploratory/Developmental Grant for Diagnostic Cancer Imaging;Fellowship;Funding;Funding Agency;Grant;high risk;Hormones;Hypertension;Hypertriglyceridemia;Individual;Institution;interest;International;Investigational Therapies;Journals;K-Series Research Career Programs;keratinocyte;Knowledge;Laboratories;Lead;lectures;Legal patent;Link;Lipids;Malignant neoplasm of prostate;Manuscripts;Mediating;Mediation;Medical center;medical schools;Medical Students;meetings;member;Mentors;Mesenchymal Stem Cells;Mitochondria;Molecular;Names;Neurosciences;novel;Obesity;Oklahoma;Oncogenes;Oncology;Ophthalmology;pandemic disease;Pathologic;Patients;Peer Review;Pharmaceutical Preparations;Pharmacology;Phosphatidylglycerols;phospholipase D2;Physiological;Physiology;Population;Positioning Attribute;posters;Principal Investigator;Process;Production;Productivity;professor;Program Evaluation;Program Research Project Grants;programs;Proliferating;protein kinase D;Psoriasis;Publications;Published Comment;Publishing;Puerto Rican;recruit;Request for Applications;Research;Research Institute;Research Personnel;response;Role;Science;Scientist;Services;Signal Pathway;Signal Transduction;Signaling Molecule;Skin;Skin Carcinoma;skin disorder;Societies;Sodium Chloride;Soldier;symposium;System;Training;tumorigenesis;United States Food and Drug Administration;United States National Institutes of Health;Universities;verticillin A;Very low density lipoprotein;very low density lipoprotein triglyceride;Veterans;vision science;Work;Zona Glomerulosa

PROJECT_TITLE: BLRD Research Career Scientist Award Application


ORG_CITY: DETROIT

ORG_NAME: JOHN D DINGELL VA MEDICAL CENTER

ORG_STATE: MI

PHR: We are proposing to continue our studies investigating molecular mechanisms of human breast cancer (HBC) growth regulation by a cellular phospho-protein CARP-1/CCAR1 that was previously identified and characterized by us. CARP-1 regulates chemotherapy (adriamycin or iressa)-dependent growth inhibition of HBC cells. We recently identified a novel, Adriamycin (ADR)-induced mechanism of apoptosis that requires CARP-1 binding with H2AX. In addition, we have found CARP-1 regulates canonical NF-κB in the presence of ADR. CARP-1 binds with IKKγ (aka NEMO). A novel, small molecule inhibitor (SMI) of CARP-1/NEMO binding enhances ADR efficacy and sensitizes HBC cells to ERK-targeting therapeutics. Thus, knowledge of the mechanisms of HBC growth suppression by SMI that targets CARP-1/NEMO binding could be exploited to enhance ADR efficacy and effectively target ADR-resistant breast cancers in the clinic.

PI_NAMEs: RISHI, ARUN KUMAR (contact)

PROJECT_TERMS: 4T1;acronyms;Adjuvant;Adriamycin PFS;Affect;anaphase-promoting complex;Apoptosis;Binding;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer therapy;Breast Cancer Treatment;Cancer Etiology;Cell Cycle;Chemoresistance;chemotherapy;Cisplatin;Clinic;Clinical Trials;combat;Coupled;Cyprinus carpio;cytokine;Data;Development;DNA;DNA Damage;Doxorubicin;Drug resistance;effective therapy;Effectiveness;EGF gene;Etoposide;Female;Gefitinib;Genotoxic Stress;genotoxicity;Growth;Healthcare;Homeostasis;hormone therapy;Human;IL2 gene;IL8 gene;improved;In Vitro;in vivo;Inflammatory;inhibitor;innovation;Interleukin-2;Knowledge;Malignant Breast Neoplasm;Mediating;MEKs;Military Personnel;Mission;Mitogen-Activated Protein Kinases;Modeling;Molecular;Molecular Mechanisms of Action;mutant;Neoadjuvant Therapy;novel;novel therapeutic intervention;Nuclear;p65;palliative;Pathway interactions;Pharmaceutical Preparations;Phenotype;Phosphoproteins;Phosphorylation;Phosphotransferases;Platinum Compounds;Poly(ADP-ribose) Polymerase Inhibitor;Prognosis;Proliferating;Publishing;Radiation therapy;receptor;Regulation;Reporting;Resistance;Role;side effect;Signal Transduction;small molecule inhibitor;Steroids;targeted treatment;Testing;Therapeutic;Therapeutic Agents;therapy development;Thyroid Gland;Tissues;TNF gene;Topoisomerase II;TP53 gene;Transducers;translational impact;treatment response;triple-negative invasive breast carcinoma;tumor;Tumor Suppression;ubiquitin-protein ligase;Veterans;Water;Women's Health;Women's mortality;Work

PROJECT_TITLE: CARP-1: A Potential Therapeutic Agent for Breast Cancer


ORG_NAME: VA  MEDICAL CENTER

PHR: Bladder cancer is the fourth most common cancer among the Veterans. Because bladder cancer is recurrent, tends to progress and requires constant monitoring, it is a major cause of pain, emotional suffering, time lost from work, poor quality of life and high medical expenses. While the bladder is a relatively accessible organ, detection of early lesions in the bladder that precede the full-fledged cancer sensitively and accurately remains challenging. This research proposal is designed to identify the specific molecular factors that characterize the early bladder lesions, so as to provide more effective ways to diagnose, predict the progression, treat or even prevent the early lesions from advancing to the late stages.

PI_NAMEs: WU, XUE-RU  (contact)

PROJECT_TERMS: Affect;Animal Model;Area;Artificial Intelligence enhanced;Attention;Automobile Driving;base;Basic Science;Behavior;Biological;Biological Markers;biomarker driven;Bladder;bladder carcinoma in situ;Bladder mucosa;cancer initiation;cancer subtypes;Carcinogens;Carcinoma in Situ;CDH1 gene;chemical carcinogenesis;Clinical;Clinical Research;cost;Cytogenetic Analysis;Data;design;Detection;Diagnosis;Differentiation and Growth;Differentiation Antigens;Dominant-Negative Mutation;Doxycycline;Early Diagnosis;effective therapy;Emotional;Environment;Epigenetic Process;Epithelium;Exhibits;experience;experimental study;Exposure to;EZH2 gene;Genetic;genetic analysis;Genetic Drift;Genetic Transcription;Genetically Engineered Mouse;Genomics;Heterogeneity;Human;immune cell infiltrate;immunological status;Immunotherapeutic agent;Immunotherapy;improved;In Situ Lesion;in vivo;insight;intravesical;Invaded;KDM1A gene;Knock-out;Knowledge;Lesion;Local Therapy;lost work time;Malignant - descriptor;Malignant neoplasm of urinary bladder;Malignant Neoplasms;Medical Care Costs;Medical center;Modeling;Molecular;molecular subtypes;Monitor;Muscle;muscle invasive bladder cancer;mutant;Neoplasm Metastasis;new therapeutic target;novel;novel diagnostics;Occupations;Oncogenic;Organ;Pain;Pathway interactions;Patients;Peroxisome Proliferator-Activated Receptors;Phenotype;Physiological;Polycomb;PPAR gamma;premalignant;prevent;Prevention;programs;progression risk;Quality of life;Radical Cystectomy;Radio;Reagent;Recurrence;Repressor Proteins;Research Proposals;Resources;response;risk prediction;risk stratification;Role;Scientist;Series;single-cell RNA sequencing;Smoking;Squamous cell carcinoma;synergism;System;Tamoxifen;Testing;therapeutic target;Tobacco smoke;TP53 gene;transcription factor;Transcriptional Regulation;Translational Research;Treatment Efficacy;treatment response;UPK2 gene;Urothelial Cell;Urothelium;Variant;Veterans

PROJECT_TITLE: BCCMA: Basic and Translational Mechanisms of Cancer Initiation of the Urothelium in Veterans Exposed to Carcinogens: Role of PPARg in theFormation and Progression of Carcinoma in situ of the Bladder


NIH_SPENDING_CATS: Biotechnology;Building Research Capacity at Institutions with Limited NIH Funding;Gene Therapy;Genetics;Human Genome;Infectious Diseases;Lung

PI_NAMEs: LIU, LIN  (contact)

PROJECT_TERMS: 2019-nCoV;Adenovirus Vector;Adopted;airway epithelium;Award;Bacteria;Biological Assay;Bronchoalveolar Lavage;Cell Line;Cells;Clinical;Clustered Regularly Interspaced Short Palindromic Repeats;Communicable Diseases;Consultations;continuous cell line;CRISPR interference;CRISPR screen;CRISPR-mediated transcriptional activation;CRISPR/Cas technology;Development;digital;DNA Microarray Chip;Epithelial Cells;gain of function;Gene Silencing;gene transfer vector;Generations;Genes;genome wide screen;genome-wide;Human;In Vitro;in vivo;Infectious Diseases Research;Institution;Knock-out;Lentivirus Vector;loss of function;Lung;Maintenance;Methods;Microarray Analysis;Molecular;Molecular Biology;Mutagenesis;Nasal Epithelium;Non-Viral Vector;Oklahoma;Organoids;overexpression;Pathway interactions;Patients;Peripheral Blood Mononuclear Cell;Phase;Reagent;Reporter;Research;Research Personnel;Resources;respiratory;Respiratory Center;Respiratory Disease;respiratory pathogen;respiratory virus;RNA Interference;Sampling;Services;single-cell RNA sequencing;Structure of parenchyma of lung;Technical Expertise;Techniques;Technology;Text;Time;Tissue Model;Training;transcriptome sequencing;transgene expression;Transgenes;Transgenic Organisms;Virus

PROJECT_TITLE: Molecular Biology Core


ORG_CITY: OKLAHOMA CITY

ORG_NAME: OKLAHOMA CITY VA MEDICAL CENTER

PHR: Alzheimer's disease (AD), a major public health concern, is a highly relevant problem for Veterans as more than half of veterans are over age 60. Veterans are at a higher risk for dementia late in life due to in-service exposures and epidemiological factors. As long as the underlying causes of AD are not well understood, it will be difficult to design effective interventions. Dr. Galvan’s research will provide important new insights into targets for interventions to prevent or treat AD and potentially other dementias.

PI_NAMEs: GALVAN, VERONICA  (contact)

PROJECT_TERMS: Age;Aging;aging brain;aging related;Agreement;Alzheimer's Disease;Alzheimer's disease brain;Alzheimer's disease model;Alzheimer's disease related dementia;Alzheimer's disease risk;Alzheimer's disease therapy;American;Amyloid beta-Protein;Area;Astrocytes;attenuation;Automobile Driving;Award;Biochemical;Biology of Aging;Blood flow;Blood Vessels;Brain;brain endothelial cell;career;Cause of Death;Cell Aging;Cells;cerebral microvasculature;cerebrovascular;Cerebrovascular Disorders;Cities;Clinic;Clinical Trials;Collaborations;Communication;Communities;Dementia;dementia risk;design;Disease;Disease Progression;doctoral student;drug testing;effective intervention;efficacy testing;Elderly;Endothelial Cells;Epidemiologic Factors;Etiology;Excision;Faculty;FDA approved;Foundations;FRAP1 gene;Functional disorder;Funding;Geroscience;Goals;Grant;Health;Health Sciences;Healthcare Systems;Heart;high risk;Holly;human model;Immunotherapy;Impaired cognition;Incidence;indexing;insight;Institution;interest;Interneurons;Intervention;Knowledge;Laboratories;Leadership;Life;Link;Medical Students;member;Mentors;Microvascular Dysfunction;minority trainee;Modeling;Molecular;Molecular Abnormality;mouse model;Mus;National Institute of Neurological Disorders and Stroke;Nature;Neurons;Neurosciences;Nitric Oxide Synthase;normal aging;novel;NuRD complex;Oklahoma;older adult;Paper;Pathogenicity;Pathology;Pharmaceutical Preparations;phase I trial;Phase II Clinical Trials;Postdoctoral Fellow;prevent;prion-like;Process;programs;proteostasis;Public Health;Research;Research Personnel;restoration;Role;Safety;Science;Scientist;Seminal;senescence;senescent cell;Services;Shock;Sirolimus;South Texas;Students;Study Section;tau aggregation;tau mutation;tau Proteins;Tauopathies;Testing;Texas;Time;Toxic effect;Training Programs;Translating;transmission process;undergraduate student;United States Department of Veterans Affairs;United States National Institutes of Health;Universities;vascular cognitive impairment and dementia;Veterans;Woman;Work


ORG_CITY: IOWA CITY

ORG_NAME: IOWA CITY VA MEDICAL CENTER

ORG_STATE: IA

PHR: The high prevalence of obesity in the Veteran population is associated with significantly elevated risk of developing metabolic and cardiovascular diseases. The current project will investigate how metabolism and the cardiovascular system are regulated, how diseases develop in obesity and identify new therapeutic strategies. This makes this project of high relevance to the Veterans who receive care at the VA.

PI_NAMEs: RAHMOUNI, KAMAL  (contact)

PROJECT_TERMS: Autonomic nervous system;Award;Blood Pressure;blood pressure control;Body Weight;Brain;Cardiovascular Diseases;Cardiovascular Physiology;cardiovascular risk factor;Cardiovascular system;career;Caring;Cell Physiology;Clinical;Clinical Treatment;Collaborations;Communities;Community Participation;Complex;Development;Disease;disorder prevention;Doctor of Philosophy;Eating;Educational process of instructing;effective therapy;Energy Metabolism;Ensure;Etiology;Event;FRAP1 gene;Future;Genes;Genetic;Genetic Transcription;Health;High Prevalence;Homeostasis;Hormones;Human;Hyperphagia;Hypertension;Hypothalamic structure;improved;insight;interdisciplinary approach;International;Iowa;Knowledge;Laboratories;Lead;learning ability;leptin receptor;Leptin resistance;Mediating;Medical;Mentors;Metabolic;Metabolic Diseases;Metabolism;Methods;military veteran;Molecular;Molecular Target;Morbidity - disease rate;mortality;mouse model;Mutation;Nerve;neuronal circuitry;neuronal excitability;Neurons;neuroregulation;next generation;novel;novel therapeutic intervention;Nutrient;Obesity;obesity development;obesity treatment;Pathway interactions;Patients;Peripheral;Physiological;Physiological Processes;Population;Process;programs;protein complex;Proteins;receptor;Regulation;Research;Research Personnel;response;Risk;Role;Running;Scientist;Services;Signal Pathway;Signal Transduction;Tissues;tool;trafficking;Training;Universities;Veterans;Work


PHR: Project Narrative: Aging is the principle risk factor for a number of conditions, including cognitive decline, Alzheimer’s, vision loss, cancer, and sarcopenia, all of which are critical issues in older veterans. As a fundamental regulator of cell function and identity, epigenetics may be a key driver of the aging process and a point of treatment to promote systemic healthy aging. Modern biological tools now allow for the elucidation of epigenomic changes across tissues and cell types within tissues. Dr. Freeman’s studies seek to understand these epigenetic processes using novel analytical approaches and animal models, complemented by advanced bioinformatic analyses. Through his collaborations, he also seeks to advance the research and training missions of the VA, extend basic biological knowledge, and identify targets for potential therapeutic manipulation. As a mentor to trainees and junior faculty, Dr. Freeman has initiated successful programs to aid junior colleagues in developing, submitting, and receiving research funding to advance their training and research.

PI_NAMEs: FREEMAN, WILLARD M (contact)

PROJECT_TERMS: Affinity Chromatography;Age;age effect;age related;age related changes;Age related macular degeneration;age-related disease;Aging;aging brain;aging mechanism;aging process;Alzheimer's Disease;analytical tool;Animal Model;anti aging;Astrocytes;Award;Basal Ganglia;base;Biochemical;Bioinformatics;Biological;Biological Assay;Biology;Blindness;Blood;Body System;Brain;Caloric Restriction;career;Caring;Cell Aging;Cell Nucleus;Cell Physiology;Cell Separation;cell type;Cells;Central Nervous System;Chromatin;Chronology;Cities;Collaborations;Colon;Communication;Communities;cost;Country;Data;Dioxygenases;Disease;DNA;DNA Methylation;DNA methylation profiling;DNA Modification Methylases;DNA Modification Process;drivers of aging;Elderly;epigenetic aging;epigenetic clock;Epigenetic Process;epigenome;epigenome editing;epigenomics;Equipment;Estradiol;Faculty;Female;Fertility;Foundations;Functional disorder;functional outcomes;Funding;Future;Gene Expression Regulation;Genetic Transcription;Genome;genome sciences;genome-wide;genomic locus;Genomic Segment;Genomics;Goals;Grant;hallmarks of aging;Health;healthy aging;Hippocampus;Impaired cognition;improved;insight;Institution;Intervention;Intervention Studies;Intestines;Joints;Knowledge;Label;Laboratory Finding;late life;male;Malignant Neoplasms;Maps;Measures;Mentors;Methylation;Microglia;Mission;Mitochondria;Modeling;Modernization;Molecular;Molecular Analysis;mouse model;Muller's cell;Mus;Muscle;Nervous System Physiology;Neurons;neurophysiology;novel;novel strategies;Nuclear;Oklahoma;old mice;Ovary;Parabiosis;Participant;Pathway interactions;Plasma;Population;Postdoctoral Fellow;Preparation;prevent;Prevention;programs;Proteins;Proteomics;Quality of life;Recording of previous events;recruit;Regulation;Rejuvenation;Research;Research Personnel;Resolution;Retina;Ribosomes;Risk Factors;RNA;sarcopenia;Scientist;senolytics;sex;Sex Differences;Sheep;Shock;Sirolimus;Site;student training;success;System;Teacher Professional Development;Techniques;Technology;Testing;Therapeutic;therapy design;Tissues;tool;Training;transcriptomics;Transgenic Mice;Translating;United States Department of Veterans Affairs;United States National Institutes of Health;Veterans;Vision research;Work


ORG_CITY: NASHVILLE

ORG_NAME: VETERANS HEALTH ADMINISTRATION

ORG_STATE: TN

PHR: Colorectal cancer remains the third leading cause of cancer-related mortality within the US and in veterans. Because of this, the VHA has issued specific directives (VHA Directive 2007-004) to improve CRC screening to detect CRC and remove pre-malignant polyps. Despite these improvements, approximately 3400 CRC cases are diagnosed yearly within the VHA system. Unfortunately, an average of 615 patients per year are still diagnosed at Stage IV, which has an overall poor prognosis. Thus, our proposed studies fit very well within the VHA cancer research portfolio. We aim to continue our VA-funded studies to understand how a novel protein, BVES, functions as a tumor suppressor in CRC. This line of research will deepen not only our understanding of BVES, but also our knowledge of the basic causes of CRC and how it advances. Our third specific aim is exceptionally clinically relevant, as we will test how BVES restoration affects tumor growth and response to treatment with traditional chemotherapy and targeted treatments in cultured human CRC and in animal models.

PI_NAMEs: WILLIAMS, CHRISTOPHER S. (contact)

PROJECT_TERMS: A kinase anchoring protein;adenoma;Adrenergic Agents;advanced disease;Affect;Anchorage-Independent Growth;Animal Model;anti-cancer research;Attenuated;attenuation;Binding;Biology;Blood Vessels;c-myc Genes;Cancer Biology;Cancer cell line;cancer diagnosis;Cancer Etiology;Cancer Model;cancer survival;cancer type;Cell membrane;cell motility;Cells;Cessation of life;Chemicals;chemotherapy;clinically relevant;Colon;Colon Carcinoma;Colonic Neoplasms;Colorectal Cancer;colorectal cancer screening;Complex;CREB1 gene;Cues;Cyclic AMP;Cyclic AMP-Dependent Protein Kinases;Data;design;Development;Diagnosis;diagnostic biomarker;Disease;Epithelial Attachment;Epithelium;Foundations;Functional disorder;Funding;Gene Expression;Gene Modified;Genetic;Grant;Growth;Healthcare Systems;Heart;Human;Hypermethylation;improved;Incidence;Inflammatory;inorganic phosphate;insight;Intervention;intestinal epithelium;Knowledge;Large Intestine Carcinoma;Malignant - descriptor;Malignant Breast Neoplasm;Malignant neoplasm of liver;Malignant neoplasm of lung;Malignant Neoplasms;malignant stomach neoplasm;Modeling;monolayer;Morphology;mortality;Motility;mouse model;Mus;Muscle Cells;nano;Neoplasm Metastasis;new therapeutic target;novel;novel diagnostics;novel therapeutics;Organoids;Pathway interactions;Patients;Phenotype;Phosphoric Monoester Hydrolases;Phosphorylation;Polyps;Positioning Attribute;potassium channel protein TREK-1;premalignant;Primary Neoplasm;Process;Prognosis;Proliferating;promoter;protein complex;Protein phosphatase;Proteins;receptor;receptor density;Regulation;Research;response;restoration;Role;Scaffolding Protein;screening program;sensor;Severe dysplasia;Signal Pathway;Signal Transduction;Signal Transduction Pathway;Stage at Diagnosis;Structure;System;targeted treatment;Techniques;Testing;Therapeutic;Therapeutic Intervention;therapeutic target;three dimensional cell culture;Tight Junctions;transcriptome sequencing;treatment response;tumor;Tumor Biology;Tumor Burden;tumor growth;tumor initiation;tumor progression;Tumor Suppressor Proteins;tumorigenesis;tumorigenic;Veterans;Veterans Health Administration;WNT Signaling Pathway;Work;Xenograft procedure

PROJECT_TITLE: Modulation of Junctional Signaling by BVES in Colorectal Carcinoma


ORG_CITY: EAST ORANGE

ORG_NAME: VA NEW JERSEY HEALTH CARE SYSTEM

PHR: Preclinical experimental model system, which accurately depict human cancer is critical in translating laboratory findings to the clinic. We discovered aberrant GRM1 expression in a large number of late- stage melanoma patients. However, current melanoma animal models do not mimic this common genetic alteration. We, therefore, propose to develop experimental mouse models reflecting this cancer-driving modification. Specifically, we will focus in melanoma brain metastasis that remains a clinically challenge aspect of this disease. A better understanding of the characteristics of brain metastases is essential to develop more effective therapeutic strategies to treat or prevent brain metastases.

PI_NAMEs: CHEN, SUZIE  (contact)

PROJECT_TERMS: Allografting;Amyotrophic Lateral Sclerosis;Animal Model;Animals;anti-cancer research;Apoptosis;Appearance;Archives;Automobile Driving;Basic Science;Biological Models;Biopsy;Blood;blood-brain barrier crossing;Brain;Cancer Patient;cancer therapy;Cell Cycle Arrest;Cell Line;Cell Transplantation;Cells;Central Nervous System;Characteristics;chemotherapeutic agent;Clinic;Clinical;Clinical Trials;Colorectal Cancer;combinatorial;Critical Pathways;Cysteine;cytokine;design;Deterioration;Development;Disease;DNA Damage;Ectopic Expression;efficacy evaluation;Etiology;Exclusion;Experimental Models;Family;FDA approved;General Population;Genes;Genotype;Glutamate Receptor;glutamatergic signaling;Glutamates;GRM1 gene;Homeostasis;Human;human model;humanized mouse;Immune;Immune checkpoint inhibitor;Immune Evasion;immune reconstitution;Immune response;Immunocompetent;Immunological Models;Immunotherapy;improved;improved outcome;In Vitro;in vivo;inhibitor;innovation;Interruption;Investigational Therapies;Laboratory Finding;Learning;Lesion;Ligands;Link;Longitudinal Studies;Luciferases;Lung;Malignant Breast Neoplasm;Malignant neoplasm of lung;Malignant Neoplasms;MAP Kinase Gene;Mediating;melanocyte;Melanoma;Melanoma Cell;Melanoma patient;metabotropic glutamate receptor type 1;Metastatic malignant neoplasm to brain;Metastatic Melanoma;military veteran;Modeling;Modification;molecular pathology;Monitor;mouse model;multidisciplinary;Mus;Mutate;Mutation;neoantigens;Neoplasm Metastasis;Neoplasms;neoplastic cell;Neurologic;Neurons;non-invasive monitor;novel strategies;NRAS gene;Operative Surgical Procedures;Organ;Paraffin;participant enrollment;Pathway interactions;patient response;Patients;peripheral blood;Pharmacotherapy;PI3K/AKT;Population;Positioning Attribute;pre-clinical;preclinical study;prevent;Primary Neoplasm;Prognosis;progression marker;Property;Quality of life;Radiation;Radiation therapy;Reactive Oxygen Species;Reduced Glutathione;Relapse;Resistance;response;response biomarker;Riluzole;Sampling;Signal Pathway;Signal Transduction;Site;small molecule;Solid Neoplasm;targeted treatment;Technology;Therapeutic;therapeutically effective;tool;Toxic effect;Transgenic Mice;Transgenic Model;Translating;translational applications;translational model;Translational Research;Translations;treatment response;tumor;tumor microenvironment;tumor progression;Work;Xenograft procedure

PROJECT_TITLE: Translational application of mouse models of melanoma brain metastases


PROJECT_TERMS: Applications Grants;Area;Award;career;Communicable Diseases;Data;Development;Extramural Activities;Funding;Grant;Infectious Diseases Research;Infrastructure;Oklahoma;Phase;Pilot Projects;Productivity;Program Research Project Grants;Research;Research Personnel;Research Project Grants;respiratory;Respiratory Center;Respiratory Disease;success;Vocational Guidance

PROJECT_TITLE: Pilot Project Grant Program


ORG_CITY: TAMPA

ORG_NAME: JAMES A. HALEY VA MEDICAL CENTER

ORG_STATE: FL

PHR: Emerging nanomedicine technologies have the potential to advance both diagnostic and therapeutic goals of diverse human diseases and already led to several products in the marketplace. Thus, nanoformulations developed in James A. Haley VA Hospital, Tampa is expected to advance the delivery of new drugs for respiratory virus infection-induced pneumonia for which elderly Veterans are a major target. Further, it is planned to investigate collaboratively with other VA scientists the potential of a novel combinatorial therapeutic approach involving nanoformulations of short interfering RNA (shRNA) against CCL20 and mesenchymal stem cells for Veterans with mild or moderate traumatic brain injury. Also, a nanofiber-scaffold-based 4D tumoroid assay will be used for clinical drug efficacy testing and personalizing cancer therapy in Veterans.

PI_NAMEs: MOHAPATRA, SHYAM S (contact)

PROJECT_TERMS: 2019-nCoV;3-Dimensional;Acceleration;Affect;American;Anti-Inflammatory Agents;Artificial Intelligence;Artificial Intelligence enhanced;Asthma;Award;bench to bedside;Biological Assay;Biology;Biopsy;Birds;career;CCL20 gene;Cell Therapy;Cells;chest computed tomography;Clinical;clinical diagnosis;clinical diagnostics;clinical training;Clinical Trials;Collaborations;combinatorial;COVID-19;Data;Development;Diagnostic;Disease;drug efficacy;Education;Educational process of instructing;efficacy testing;Elderly;Endowment;experience;Extramural Activities;Florida;Formulation;Funding;Future;General Population;Goals;graduate student;Health;Healthcare;Hospitals;human disease;Hypersensitivity;Image Enhancement;Immunocompetent;Immunology;improved;In Vitro;in vivo;Incidence;indexing;Individual;Industry Collaboration;Inflammation;Inflammatory;influenza infection;inhibitor;innovation;International;Investments;Lead;Legal patent;Liposomes;Malignant neoplasm of brain;Malignant neoplasm of lung;Medicine;Mesenchymal Stem Cells;Methods;Modeling;mouse model;Mus;nano;Nanofiber Scaffold;nanoformulation;nanomedicine;nanomicelles;nanoscale;nanosystems;nanotherapeutic;Nature;Nerve Regeneration;novel;novel diagnostics;novel therapeutics;novel virus;Nursing Faculty;Oligosaccharides;Oncolytic;pandemic disease;particle;Peptides;personalized cancer therapy;Phospholipids;Pneumonia;prevent;professor;Property;prophylactic;Prophylactic treatment;Publications;Reporting;Research;Research Activity;Research Personnel;Research Support;respiratory infection virus;Respiratory syncytial virus;Respiratory Syncytial Virus Infections;Safety;SARS-CoV-2 antiviral;SARS-CoV-2 infection;Scientist;Seminal;Small Interfering RNA;stem cell therapy;System;Technology;Testing;Therapeutic;translational medicine;Translations;Traumatic Brain Injury;United States Department of Veterans Affairs;United States National Institutes of Health;Universities;Veterans;Viral;Viral Respiratory Tract Infection;Virus Diseases;Work

PROJECT_TITLE: BLRD Merit Review Research Career Scientist Award


ORG_CITY: INDIANAPOLIS

ORG_NAME: RLR VA MEDICAL CENTER

ORG_STATE: IN

PHR: A million Veterans suffer from osteoporosis, while another 2.5 million are osteopenic. Worse yet, the burden is expected to rise given the senescing Veteran population. Beyond age, other lifestyle factors make Veterans particularly susceptible to osteoporosis, including increased prevalence of smoking, alcohol consumption, and physical inactivity. Moreover, many Vietnam and Desert Storm Veterans were exposed to environmental factors that put them at much greater risk for developing bone and joint disease. Another issue facing many returning Veterans is spinal cord injury (SCI) and other battlefield-related injuries resulting in neuromuscular impairment. Those conditions result in disuse-osteoporosis, and progress made in neuromuscular rehabilitation can be offset or even nullified by degenerative changes in the bone. We are working on exciting new approaches to preserving bone mass, structure, and mechanical integrity in the presence of neuromuscular impairment, which we believe will have significant translational capacity to impaired and osteoporotic Veterans.

PI_NAMEs: ROBLING, ALEXANDER G (contact)

PROJECT_TERMS: Address;Age;Age Years;agent orange;Alcohol consumption;American;Anatomy;Antibodies;arthropathies;Award;Basic Science;Bed rest;Biochemical;Biography;Biology;Body Weight;bone;Bone Diseases;bone disuse atrophy;bone health;bone loss;bone mass;bone metabolism;bone preservation;bone strength;Bone Tissue;career;Cell Physiology;Cellular biology;Compensation;Country;Data;Dioxins;disability;Disease;Dose;driving force;Drug usage;Environmental Risk Factor;Event;Exposure to;Fracture;Funding;Future;Genes;Genetic;genetic linkage;genomic locus;Glucocorticoids;Goals;Health;Healthcare;Herbicides;Home;Homing;Hormonal;human disease;Hydrolase;Hyperostosis;Immunosuppression;Impairment;improved;Indiana;Inflammation;inhibitor;Injury;insight;Investigation;Journals;lifestyle factors;long bone;Measurement;mechanical load;mechanical signal;Mechanical Stimulation;Mechanics;mechanotransduction;Mediator;medical schools;Medicine;member;Metabolic;Middle East;Military Personnel;military veteran;Minerals;Mission;mouse genome;Mus;Muscle;Musculoskeletal;Mutation;Nature;neuromuscular;neuromuscular function;neuromuscular rehabilitation;novel strategies;Osteoblasts;Osteocytes;Osteogenesis;Osteoporosis;osteoporosis with pathological fracture;Osteoporotic;Paper;Paralysed;Pathway interactions;Patients;Persian Gulf;Persons;physical inactivity;Play;Porosity;Predisposition;prevent;Process;programs;Property;Proteins;PTH gene;Publications;Publishing;Quantitative Trait Loci;receptor;Rehabilitation therapy;Reporting;Research;Research Personnel;response;Risk;Role;Scientist;Seminal;Serum;Side;side effect;Signal Pathway;Signal Transduction;skeletal;skeletal disorder;Skeleton;smoking prevalence;Soldier;Spinal cord injury;Stimulus;Structure;Techniques;Testosterone;Tetrachlorodibenzodioxin;Therapeutic;therapeutic target;therapy design;translational medicine;translational potential;Translational Research;Universities;Van Buchem disease;Veterans;Vietnam;War;Wasting Syndrome;WNT Signaling Pathway;Work


ORG_CITY: LOS ANGELES

ORG_NAME: VA GREATER LOS ANGELES HEALTHCARE SYSTEM

ORG_STATE: CA

PHR: TOR kinase inhibitors are novel drugs with exciting and impressive antitumor activity in preclinical studies. It would thus, be critical to understand the mechanisms by which tumor cells respond to these agents such that they can be used most effectively used in the clinic. This proposal seeks to understand the mechanisms of tumor cell resistance to mTOR inhibitors and evaluate novel targeted therapies in combination with mTOR inhibition. These studies may benefit both Veteran and non-Veteran populations and provide additional future treatment options. Brain and breast cancers are relatively frequently encountered in our Veterans and current treatment protocols have not advanced significantly. The development of additional treatments may improve the current prognosis for patients and also find utility in the treatment of lung and prostate cancers, which are common in our Veteran population.

PI_NAMEs: GERA, JOSEPH F (contact)

PROJECT_TERMS: Address;Adenosine;Adult;Animals;antitumor effect;Arginine;Binding;Binding Sites;Biochemical;Biogenesis;Breast Cancer Model;cancer drug resistance;cancer type;Cell Survival;Clinic;clinically actionable;clinically relevant;Complex;Cyclic AMP-Dependent Protein Kinases;Data;Development;disease model;Drug resistance;Drug Targeting;Effectiveness;efficacy evaluation;Epidermal Growth Factor Receptor;evaluation/testing;experimental study;FDA approved;Feedback;FRAP1 gene;Future;Genetic;Growth Factor;hnRNP A1;Holoenzymes;Hyperactivity;improved;in vivo;inhibitor;inhibitor therapy;Internal Ribosome Entry Site;kinase inhibitor;Link;Malignant Breast Neoplasm;Malignant neoplasm of brain;Malignant neoplasm of lung;Malignant neoplasm of prostate;Malignant Neoplasms;Mediating;Mediator;Messenger RNA;Methylation;Methyltransferase;military veteran;Modification;Molecular;mouse model;mRNA Translation;mTOR inhibition;mTOR Inhibitor;Mutation;neoplastic cell;new therapeutic target;novel;novel therapeutics;Nutrient;Outcome;Pathway interactions;patient prognosis;Patients;Pharmaceutical Preparations;Phase I Clinical Trials;Phosphotransferases;PI3K/AKT;PIK3CG gene;Population;pre-clinical;preclinical study;Preclinical Testing;Protein Biosynthesis;Protein Synthesis Inhibition;Proteins;Proto-Oncogene Proteins c-akt;PTEN gene;Receptor Protein-Tyrosine Kinases;Recurrence;Regulation;Reporting;Resistance;resistance mechanism;Ribosomes;Role;Signal Transduction;Sirolimus;Site;small molecule inhibitor;targeted treatment;Testing;Transcript;Translation Initiation;Translations;Treatment Protocols;triple-negative invasive breast carcinoma;tumor;tumor growth;Veterans

PROJECT_TITLE: Mechanisms of Resistance to mTOR Targeted Therapies


ORG_CITY: PALO ALTO

ORG_NAME: VETERANS ADMIN PALO ALTO HEALTH CARE SYS

PHR: Aging is the single greatest risk factor for many chronic diseases and thus is a major contributor to morbidity in the VA population. Our overarching research goal is to understand how chromatin regulatory mechanisms influence nuclear and epigenetic programs, and how de-regulation of these mechanisms contributes to aging and disease. We focus on the mammalian SIRT6 and SIRT7 genes, members of the evolutionarily conserved “Sirtuin” gene family that regulates lifespan, metabolism, and stress resistance in many organisms. My lab has been at the forefront of studying the molecular mechanisms of SIRT6 and SIRT7 and their links to aging, cancer, and stress-resistance. We have pioneered biochemical and genomic approaches that established that SIRT6 and SIRT7 are highly selective histone deacetylase enzymes and identified their first known physiologic substrates. Our discoveries opened up the field for functional characterization of these hitherto orphan enzymes, by my lab and many others. We uncovered novel mechanisms of SIRT6 in preventing genomic instability, telomere dysfunction, DNA damage, heterochromatin dysfunction, aging-related epigenetic programs, and cellular senescence. We also elucidated functions of SIRT7 in regulating epigenetic oncogenic programs, tumor growth and metastasis, metabolic homeostasis, and non-alcoholic fatty liver disease. We have also had a longstanding interest in understanding cellular senescence and its roles in aging and age-related disease pathologies. We have provided many insights into novel triggers of cellular senescence and their regulation by SIRT6 and SIRT7, including heterochromatin defects and accumulation of pathogenic transcripts from non-coding, repetitive DNA sequences. Our ongoing research activities continue to probe the biological functions of SIRT6 and SIRT7, focusing in several areas: (1) Elucidate novel biochemical activities and substrates, molecular interactions, and genomic and epigenomic targets of SIRT6 and SIRT7; (2) Determine the effects of activating or inhibiting SIRT6 and SIRT7 on aging processes in cellular systems and in vivo mouse models; (3) Determine if increased levels of SIRT6 or SIRT7 can protect against pathologies of aging and potentially extend lifespan; (4) Discover novel mechanistic links of these genes to diseases of high impact to the VA patient population including metabolic, inflammatory, neurodegenerative, musculoskeletal, and neoplastic disorders. Importantly, in addition to elucidating the specific functions of SIRT6 and SIRT7, our research on these genes continues to address fundamental questions in the biology of aging, including: (1) Molecular mechanisms of genomic instability, cellular aging, and immunosenescence, and the physiologic impacts of these processes on functional changes of aging and disease; (2) The potential for increased activity of SIRT6 or SIRT7, using in vivo mouse models, to protect against aging-related pathologies and improve health; (3) Epigenetic mechanisms in aging and cancer biology, which, unlike genetic mutations, can be reversible and offer potential targets for developing novel therapeutic strategies; (4) Novel mechanistic and physiologic interplay of metabolic changes and pathologies of aging; (5) Overlapping or opposing molecular processes in aging physiology and cancer.  Together, our work has a broad impact on research into molecular mechanisms of aging, metabolic disorders, cancer, and other aging-related pathologies, and promises to continue to provide new insights that may be translated into therapeutic strategies for diseases that impact Veterans’ health. .

PI_NAMEs: CHUA, KATRIN F. (contact)

PROJECT_TERMS: Address;age-related disease;aged;Aging;aging mechanism;aging process;aging related;Area;Automobile Driving;Award;Binding;Biochemical;Biochemistry;Biological Process;Biology;Biology of Aging;Cancer Biology;Cardiovascular Diseases;career;Cell Aging;Cell Physiology;Cells;Chromatin;Chronic Disease;Collaborations;Defect;Diabetes Mellitus;Direct Costs;Disease;DNA Damage;DNA Sequence;DNA Sequence Alteration;Enzymes;epigenetic aging;Epigenetic Process;epigenomics;extend lifespan;Functional disorder;Funding;Future;Gene Expression Regulation;Gene Family;gene network;Genes;Genetic Transcription;Genomic approach;Genomic Instability;Genomics;Goals;Grant;Health;Healthcare;Heart Diseases;Heterochromatin;Histone Deacetylase;Histone Deacetylation;histone methyltransferase;Homeostasis;Human;human old age (65+);immunosenescence;Impairment;improved;in vivo;Inflammation;Inflammatory;insight;interest;Journals;Lead;life span;Link;Liver diseases;Lysine;Malignant Neoplasms;Mediating;member;Metabolic;Metabolic Diseases;Metabolic stress;Metabolism;Methylation;military veteran;Molecular;Molecular Biology;Morbidity - disease rate;mouse model;muscle regeneration;Musculoskeletal;Nature;Neoplasm Metastasis;neoplastic;Nerve Degeneration;non-alcoholic fatty liver disease;novel;novel therapeutic intervention;Nuclear;Obesity;Oncogenic;Organism;Orphan;Oxidative Stress;Paper;Pathogenicity;Pathologic;Pathology;Pathway interactions;patient population;Physiological;Physiology;Population;prevent;Process;professor;programs;Proteins;Proteomics;Publishing;Reader;Regulation;Research;Research Activity;Research Personnel;Resistance;Risk Factors;Role;Scientist;senescence;Signal Pathway;Signal Transduction;Sirtuins;Squamous Cell Lung Carcinoma;stem cell biology;Stress;structural biology;System;targeted treatment;telomere;Therapeutic;Tissues;Transcript;Translating;tumor growth;United States National Institutes of Health;Universities;Untranslated RNA;Veterans;Work


ORG_CITY: MIAMI

ORG_NAME: MIAMI VA HEALTH CARE SYSTEM

PHR: Dr. El-Rifai research focuses on molecular studies of gastric cancer and esophageal adenocarcinoma (EAC). Gastric carcinoma is the third most common cause of cancer related-death worldwide. According to the World Health Organization, National Cancer Institute, and epidemiological data, individuals with chronic H. pylori infection carry a 3 - to-6 fold higher risk of developing gastric cancer. Recent studies of U.S soldiers deployed to the Middle East and Far East have shown that the incidence of H. pylori infection was 7.3 percent per year compared to 2.5 percent of U.S. military recruits living at home, which represents a major increase in risk. Furthermore, the incidence of gastroesophageal reflux disease, the main risk factor for EAC, is significantly higher in our veterans’ population than general population. Taken together, the molecular and translational research activities of Dr. El-Rifai lab are highly pertinent to our Veterans’ health.

PI_NAMEs: EL-RIFAI, WAEL  (contact)

PROJECT_TERMS: 20q;3-Dimensional;Animal Model;anti-cancer research;Anti-Inflammatory Agents;Antineoplastic Agents;antioxidant enzyme;Antioxidants;Area;aurora kinase A;Award;Barrett Esophagus;Barrett's Tumorigenesis;Basic Science;Belief;beta catenin;Binding;Bioinformatics;Biological;Biology;Cancer Biology;cancer cell;Cancer Etiology;cancer genetics;carcinogenesis;career;Cell Survival;Cellular biology;Cessation of life;Chronic;Clinical;clinical investigation;Clinical Oncology;Clinical Research;Clinical Trials;Communication;comparative genomic hybridization;Complex;Comprehensive Cancer Center;Cooperative Research and Development Agreement;Development;Disease;DNA Damage;DNA Methylation;DNA Repair;DNA Sequence Alteration;Doctor of Medicine;Doctor of Philosophy;Drug resistance;epidemiologic data;Epigenetic Process;epigenomics;Esophageal Adenocarcinoma;experience;Faculty;Far East;Finland;Fluorescent in Situ Hybridization;FRAP1 gene;functional genomics;Funding;Gastric and esophageal adenocarcinomas;gastric tumorigenesis;Gastroenterology;gastroesophageal cancer;Gastroesophageal reflux disease;gastrointestinal;General Population;Genes;Genetic;Genetic Transcription;Goals;graduate student;Health;Helicobacter Infections;Helicobacter pylori;high risk;histone methylation;Home;Human;Human Resources;human tissue;in vitro Assay;Incidence;indexing;Individual;Infection;Inflammation;innovation;interest;International;Journals;Knockout Mice;Laboratories;Leadership;Link;Location;Malignant neoplasm of esophagus;Malignant neoplasm of gastrointestinal tract;Malignant Neoplasms;malignant stomach neoplasm;Mediating;Medical Oncology;medical schools;meetings;member;Mentors;Metaphase;Methylation;MicroRNAs;Middle East;Military Personnel;military veteran;Modeling;Molecular;Molecular Cytogenetics;mouse model;Mus;National Cancer Institute;Nature;new therapeutic target;next generation sequencing;NF-E2-related factor 2;NF-kappa B;novel;novel strategies;novel therapeutic intervention;nuclear factor-erythroid 2;Oncogenes;Oncogenic;Oncology;Operative Surgical Procedures;Organoids;Outcome;overexpression;Oxidation-Reduction;Oxidative Stress;Oxidative Stress Induction;Pathology;Peer Review;Peptides;Pharmacologic Substance;Play;Population;Positioning Attribute;Postdoctoral Fellow;professor;Program Development;programs;Publications;Publishing;Radiation Oncology;recruit;Reflux;Research;Research Activity;research and development;Research Training;Resource Allocation;response;Risk;Risk Factors;Role;Sampling;Scientist;serial analysis of gene expression;Signal Transduction;Soldier;Solid Neoplasm;STAT3 gene;statistics;Stomach Carcinoma;targeted treatment;Testing;TFF1 gene;Therapeutic;Tissue Sample;TP53 gene;Training;transcription factor;transcriptome sequencing;Translational Research;Translations;Tumor Biology;Tumor Necrosis Factor Receptor;Tumor Suppression;Tumor Suppressor Genes;Tumor Suppressor Proteins;tumorigenesis;tumorigenic;undergraduate student;United States National Academy of Sciences;Universities;upper gastrointestinal cancer;Veterans;Work;World Health Organization


ORG_CITY: SEATTLE

ORG_NAME: VA PUGET SOUND HEALTHCARE SYSTEM

ORG_STATE: WA

PHR: Prostate cancer is the most common solid tumor malignancy in our veterans’ population, with 13,000 veterans diagnosed annually. In addition, currently VA facilities are treating about 11,000 men with lethal metastatic castration resistant prostate cancer (CRPC). Developing pathways that could be co-targeted along with direct AR-targeting is a current translational and clinical priority, and a key focus of our work. Metabolic reprogramming to one that promotes disease progression, contributes to treatment resistance and leads to recurrent disease. This proposal will define the changes in metabolic reprograming that continue to drive disease progression through the androgen receptor signaling pathway. Importantly it will use two new and novel therapies we have developed to reprogram tumor metabolism and suppress androgen receptor expression and signaling and subsequent tumor growth in lethal prostate cancer.

PI_NAMEs: PLYMATE, STEPHEN R. (contact)

PROJECT_TERMS: 5'-AMP-activated protein kinase;abiraterone;Acetyl-CoA Carboxylase;Addendum;Address;Adenosine Monophosphate;aerobic glycolysis;Affect;Androgen Antagonists;androgen deprivation therapy;androgen independent prostate cancer;Androgen Receptor;Androgen Suppression;Automobile Driving;Benign;cancer cell;Cancer Patient;Castration;Cell membrane;Cell Physiology;Cell Proliferation;Cell Respiration;Cells;Clinical;clinical development;Combined Modality Therapy;constitutive active receptor;Data;Development;Diagnosis;Disease;Disease Progression;enzalutamide;Enzymes;Epithelium;fatty acid metabolism;Fatty-acid synthase;Genes;Genetic;Genetic Transcription;Growth;Immunotherapy;improved;In Vitro;in vivo;Length;lipid biosynthesis;lipid metabolism;Malignant - descriptor;Malignant neoplasm of prostate;Malignant Neoplasms;membrane synthesis;men;Metabolic;Metabolism;metabolome;Metastatic Prostate Cancer;military veteran;Mitochondria;Modeling;Monounsaturated Fatty Acids;new therapeutic target;novel drug class;novel therapeutics;optimal treatments;Output;Pathway interactions;Patients;Poly(ADP-ribose) Polymerase Inhibitor;Post-Transcriptional Regulation;precision oncology;Process;programs;Progress Reports;Proliferating;Prostate;prostate cancer cell;prostate cancer progression;Prostatic Neoplasms;Protein Dephosphorylation;Protein Isoforms;Protein Kinase;Proteins;Publishing;receptor expression;Receptor Signaling;Recurrent disease;Recurrent tumor;Resistance;Role;Serine;Signal Pathway;Solid Neoplasm;targeted agent;targeted treatment;Therapeutic;therapy development;therapy resistant;Tissue Microarray;tumor;tumor growth;tumor metabolism;tumor progression;Universities;Variant;Veterans;Washington;Work

PROJECT_TITLE: Targeting the Metabolome in Androgen Receptor-driven Castration-resistant Prostate Cancer


ORG_CITY: CHICAGO

ORG_NAME: JESSE BROWN VA MEDICAL CENTER

ORG_STATE: IL

PHR: Project Narrative Veterans suffering from post-traumatic stress disorder (PTSD) experience high anxiety levels, which increases their susceptibility to alcohol and drug addiction. As a result, alcohol use disorder (AUD) is one of the major health concerns for veterans. This research program will elucidate various epigenetic mechanisms in brain circuitry associated with the development of alcohol addiction in concert with anxiety-like behaviors. This research will inform the development of novel pharmacological therapies that target these molecular pathways in order to treat AUD, both with and without comorbid anxiety.

PI_NAMEs: PANDEY, SUBHASH C. (contact)

PROJECT_TERMS: Acute;Adolescence;Adolescent;adolescent alcohol exposure;adolescent binge drinking;Adult;Alcohol abuse;alcohol abuse therapy;Alcohol consumption;Alcohol dependence;alcohol effect;alcohol exposure;alcohol research;alcohol use disorder;alcohol use initiation;Alcohol withdrawal syndrome;Amygdaloid structure;Animal Model;Anti-Anxiety Agents;Anxiety;Anxiety Disorders;anxiety-like behavior;Area;ATAC-seq;Autopsy;Award;Behavior;behavioral phenotyping;Big Data;Brain;brain circuitry;career;Caring;Cell Physiology;Chemicals;ChIP-seq;Chronic;Clinical Research;comorbidity;Dependence;Development;DNA;DNA Methylation;drinking behavior;Drug abuse;Drug Addiction;Drug Design;Education;Epigenetic Process;Event;experience;experimental study;Functional disorder;Funding;Future;Gene Expression;General Population;Genes;Genome;Grant;Health;Healthcare;Histone Acetylation;Histones;Human;Individual;Intervention;Laboratories;Laboratory Research;Life;Maintenance;mature animal;Methylation;Mission;Modification;Molecular;molecular targeted therapies;National Institute on Alcohol Abuse and Alcoholism;neural circuit;Neurobiology;Neurosciences;next generation;novel;Pathway interactions;Patient Care;Patients;pharmacologic;Physiology;Population;Post-Traumatic Stress Disorders;Postdoctoral Fellow;pre-doctoral;preclinical study;Predisposition;Process;programs;Research;Research Personnel;Research Project Grants;Research Training;Risk Factors;Role;Scientist;Series;Shapes;substance use;Symptoms;Synaptic plasticity;therapeutic development;Training;transcriptome sequencing;transcriptomics;Translating;Translations;underage drinking;United States National Institutes of Health;Untranslated RNA;Veterans;withdrawal-induced anxiety;Work


ADMINISTERING_IC: HL

IC_NAME: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE

NIH_SPENDING_CATS: Aging;Behavioral and Social Science;Cardiovascular;Climate-Related Exposures and Conditions;Clinical Research;Health Disparities Research;Health Disparities and Racial or Ethnic Minority Health Research;Health Services;Heart Disease;Machine Learning and Artificial Intelligence;Prevention;Social Determinants of Health

ORG_CITY: NEW YORK

ORG_NAME: WEILL MEDICAL COLL OF CORNELL UNIV

PHR: PUBLIC HEALTH STATEMENT The short-term effects of extreme weather such as hurricanes on cardiovascular disease (CVD) are well-docu- mented but long-term CVD effects are unknown, likely leading to adverse outcomes, particularly for vulnerable residents whose limited resources often mean staying in place. This project will identify hurricane victims at high risk of CVD mortality and morbidity by measuring Hurricane Sandy’s impact on New York City in 2012, and will lay the groundwork for a validation study using Medicare claims data from the devastating 2017 hurri- cane season – the costliest in US history. Our goal is to inform individual- and population-level pre- and post- disaster management strategies and assure that they address the need for interventions among those at great- est risk of adverse CVD outcomes from hurricanes in order to mitigate these risks. 1

PI_NAMEs: GHOSH, ARNAB KUMAR (contact)

PROGRAM_OFFICER_NAME: SIDDIQUI, AYESHA SAEED

PROJECT_TERMS: Address;adverse outcome;Affect;American;authority;Authorization documentation;Award;beneficiary;Cardiovascular Diseases;cardiovascular disorder risk;cardiovascular health;career;Censuses;Cessation of life;climate change;Clinical;Communities;Companions;Congresses;Coronary heart disease;cost;Cox Models;Cox Proportional Hazards Models;Data;Data Set;Development;Disaster Planning;Disasters;Disease Management;Disease Outcome;Disparity;Durable Medical Equipment;Economics;Emergency Care;Emergency Situation;empowerment;Epidemiology;Event;experience;extreme weather;Floods;Frequencies;Functional impairment;Future;Goals;Health;health care availability;health equity;Health Services Research;Health system;Heart failure;high risk;high risk population;human old age (65+);Hurricane;improved;indexing;Individual;Intervention;Knowledge;Lead;Learning;Link;Long-Term Effects;low socioeconomic status;Machine Learning;Measures;Medical;Medicare;Medicare claim;Mentors;Methods;Modeling;Morbidity - disease rate;mortality;Myocardial Infarction;Natural Disasters;Natural experiment;neighborhood disadvantage;Neighborhoods;New York City;Older Population;Outcome;Physicians;Policies;Population;population health;predictive tools;Prevalence;programs;Public Health;Puerto Rico;Recording of previous events;Recovery;Research;Research Personnel;Resources;restoration;Risk;risk mitigation;risk prediction;risk prediction model;Sampling;Science;Scientist;Seasons;Services;skills;social;social epidemiology;Socioeconomic Status;spatiotemporal;Stroke;Survival Analysis;System;Techniques;Training;United States Dept. of Health and Human Services;validation studies;Vulnerable Populations;Work

PROJECT_TITLE: Understanding the long-term effects of hurricanes on cardiovascular health and outcomes

STUDY_SECTION: MCBS

STUDY_SECTION_NAME: NHLBI Mentored Clinical and Basic Science Study Section[MCBS(OA)]


PHR: US veterans with pulmonary arterial hypertension (PAH) are at a high risk for death. PAH is currently an incurable condition with higher prevalaence in veterans compared with the general population. BMPR2 gene mutations are the most important genetic risk factor for this disease. New research suggests that individuals with these mutations can develop PAH after lung inflammation when an abnormal growth of the inner layers of blood vessels (neointima) occurs. The neointima causes high blood pressure in the lungs, followed by heart failure and death. This proposal seeks to understand how BMPR2 mutations cause this dangerous transformation of pulmonary blood vessels so that life-saving therapies (targeting the neointima) may ultimately be developed.

PI_NAMEs: NICOLLS, MARK ROBERT (contact)

PROJECT_TERMS: Animals;Arachidonate 5-Lipoxygenase;Arteries;arteriole;Atlases;Automobile Driving;Binding;bioinformatics tool;biomarker validation;Blood capillaries;Blood Vessels;bone morphogenetic protein receptors;Cell Lineage;Cell Proliferation;Cell Therapy;cell transformation;Cells;Cellular biology;Cessation of life;Characteristics;chromatin immunoprecipitation;Chronic;Chronic pulmonary heart disease;Clinical;Coupled;Cues;Dangerousness;Data;Disease;Disease Pathway;DNA Sequence Alteration;druggable target;Endothelial Cells;Endothelium;Epigenetic Process;Fluorescent in Situ Hybridization;Future;Gene Mutation;General Population;Genes;Genetic;Genetic Markers;genetic risk factor;Genetic Transcription;genetic variant;Germ-Line Mutation;Goals;Grant;Growth;Health;Heart failure;hemodynamics;Heterozygote;High Prevalence;high risk;Histology;Human;human disease;Hypertension;IL6ST gene;Immunofluorescence Immunologic;Individual;Inflammation;Inflammation Mediators;Inflammatory;Inherited;Interleukin-1;Interleukin-6;Lead;Lesion;Life;Link;Lung;lung pressure;Maintenance;Mediating;Modeling;Molds;Molecular;Molecular Target;mortality risk;mutant;Mutation;mutation carrier;NF-kappa B;novel;Nuclear;p65;Pathologic Processes;Pathway interactions;Patients;phase II trial;Phenotype;Population;Post-Translational Protein Processing;pressure;Prognosis;programs;Proliferating;pulmonary arterial hypertension;pulmonary arterial pressure;Pulmonary artery structure;Pulmonary Hypertension;Pulmonary Inflammation;Rattus;receptor;Research;right ventricular failure;Signal Pathway;Signal Transduction;single molecule;single-cell RNA sequencing;Smooth Muscle Myocytes;System;Techniques;Testing;Therapeutic;therapeutic target;Transcription Coactivator;Transcriptional Regulation;transcriptome;transcriptomics;Transforming Growth Factor beta;Transposase;Tunica Intima;Vascular Diseases;vascular inflammation;Vascular remodeling;Veterans;Veterans Health Administration

PROJECT_TITLE: BMPR2 mutations, Neointimal Transformation and Pulmonary Arterial Hypertension


ORG_CITY: BALTIMORE

ORG_NAME: BALTIMORE VA MEDICAL CENTER

ORG_STATE: MD

PHR: With an increasing number of women serving in the military, there is a significant need to effectively manage active duty and Veteran breast cancer patients. Despite progress in early cancer screening and improving systemic therapies; the percentage of breast cancer patients developing brain metastasis is increasing - particularly those diagnosed with the human epidermal growth factor receptor 2 (HER2)-positive or triple-negative breast cancer (TNBC) subtype. Breast cancer patients harboring brain metastases face a dismal prognosis; indeed, in the case of TNBC patients, median survival after detection of metastatic disease can be as short as 5 months. Thus, there is an urgent need to identify new therapeutic targets for breast tumor cells residing in the brain microenvironment and develop innovative drug delivery strategies for effective killing of these cells without harming nearby normal brain neurons and glial cells.

PI_NAMEs: KIM, ANTHONY J. (contact)

PROJECT_TERMS: ABCB1 gene;Abraxane;active duty;Adhesives;Affinity;Animals;Antineoplastic Agents;Binding;Biodistribution;Biological;Blood - brain barrier anatomy;blood-brain barrier disruption;blood-brain tumor barrier;Brain;Brain Neoplasms;brain parenchyma;Breast;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer Treatment;cancer cell;cancer subtypes;cancer type;Capillary Endothelial Cell;cell killing;Cell Surface Receptors;cerebral capillary;Charge;Clinical;clinical development;clinical translation;Clinical Trials;cytotoxicity;design;Detection;Development;Diagnosis;Diffuse;Disease;Distant;drug clearance;Drug Combinations;Drug Delivery Systems;Drug Efflux;Drug Kinetics;drug standard;efflux pump;Electrostatics;Engineering;Epidermal Growth Factor Receptor;Extracellular Space;Face;Fatty acid glycerol esters;FDA approved;Female;Focused Ultrasound;Focused Ultrasound Therapy;Formulation;glymphatic system;Goals;Human;Human Resources;Immunocompetent;improved;In Vitro;in vivo;innovation;instrument;interstitial;Intracranial Neoplasms;intravenous administration;Kinetics;Magnetic Resonance Imaging;male;Malignant Breast Neoplasm;Malignant neoplasm of lung;mammary;Mammary Neoplasms;Maximum Tolerated Dose;MDA MB 231;Mediating;Melanoma;member;Metastatic breast cancer;Metastatic malignant neoplasm to brain;Microfluidics;Military Personnel;military service;Modeling;Monoclonal Antibodies;Multi-Drug Resistance;Mus;nanoparticle;nanoparticle delivery;nanotherapeutic;Neoplasm Metastasis;neoplastic cell;Neuroglia;Neurons;new therapeutic target;novel therapeutics;Organ;overexpression;Paclitaxel;Patients;Penetration;Pharmaceutical Preparations;Pharmacotherapy;Positioning Attribute;pressure;Process;Production;Prognosis;programmed cell death ligand 1;Property;Pump;receptor;Recurrence;Regimen;Research;Safety;safety assessment;Screening for cancer;Specimen;standard care;Surface Properties;System;Systemic Therapy;Technology;Testing;Therapeutic;therapeutic nanoparticles;Tissues;Treatment Efficacy;treatment strategy;triple-negative invasive breast carcinoma;tumor;tumor growth;Tumor Necrosis Factor Receptor;Tumor Tissue;United States;Veterans;Woman;Work;Xenograft Model

PROJECT_TITLE: Novel drug delivery strategies for treatment of breast cancer brain metastases


PHR: The proposed research is relevant to the health of veterans and the mission of the Department of Veterans Affairs because understanding the mechanisms by which combination regimens enhance immune responses in pancreatic tumors may ultimately result in improvement in the survival of pancreatic cancer patients.

PI_NAMEs: MUNSHI, HIDAYATULLAH G. (contact)

PROJECT_TERMS: 3' Untranslated Regions;anti-PD1 antibodies;Antitumor Response;arginase;Binding;cancer cell;CD8-Positive T-Lymphocytes;cell type;Cellular Immunity;Cellular immunotherapy;Characteristics;chemokine;Chemotactic Factors;Clinical;Clinical Research;clinical translation;Combined Modality Therapy;CTLA4 gene;CXCL10 gene;CXCL9 gene;cytokine;Development;effector T cell;efficacy evaluation;Elements;Enzymes;Eukaryotic Initiation Factors;exhaustion;expectation;Genes;Goals;Health;Human;Immune response;Immunologics;Immunosuppression;Immunotherapy;improved;improved outcome;in vivo;Infiltration;inhibitor;innovation;insight;interest;Macrophage;Malignant neoplasm of pancreas;Mediating;Mission;mouse model;mRNA Translation;novel;novel therapeutic intervention;Outcome;pancreatic cancer patients;Pancreatic Ductal Adenocarcinoma;pancreatic ductal adenocarcinoma cell;pancreatic ductal adenocarcinoma model;pancreatic neoplasm;Pathway interactions;Patients;PD-1 inhibitors;Phosphorylation;Phosphotransferases;programmed cell death ligand 1;programmed cell death protein 1;protein expression;Proteins;Reaction;Regimen;Regulation;Reporting;Research;response;Role;Slice;Solid Neoplasm;synergism;T cell infiltration;T-Lymphocyte;targeted treatment;Testing;therapy resistant;trafficking;Transgenic Mice;Transgenic Organisms;tumor;tumor growth;Tumor-associated macrophages;tumor-immune system interactions;United States Department of Veterans Affairs;Veterans

PROJECT_TITLE: Role of MNK kinase pathway in regulating tumor immune microenvironment in pancreatic cancer


PHR: Urothelial carcinoma (bladder cancer) is the fourth most common cancer in the VHA accounting but with fewer than half of patients with Stage IV cancer are alive at 12 months. From our 2016 VA Merit Award, we translated the results of our research into a nationwide clinical trial to treat patients with metastatic bladder cancer with epigenetic therapy (tazemetostat) and anti-PD1 therapy (pembrolizumab). In this current proposal, we seek to further understand how chromatin regulation is involved immune evasion in bladder cancer. Our central hypothesis is that loss of function mutations of COMPASS create epigenetic imbalance at histone sites facilitating immune evasion by Enhancer of Zeste-2 (EZH2). In this proposal, we will investigate EZH2- mediated repression of antigen presentation, chemokine production and lymphocyte recruitment, and enhanced Tregulatory activity to identify new immunotherapy strategies for treatment of Veterans.

PI_NAMEs: MEEKS, JOSHUA JAMES (contact)

PROJECT_TERMS: Accounting;Aftercare;anti-PD1 therapy;anti-tumor immune response;Antigen Presentation;Award;bench-to-bedside translation;Bladder;Bladder Neoplasm;Blocking Antibodies;cancer cell;Cancer Etiology;Cancer Model;cancer survival;Cancer Therapy Evaluation Program;Carcinogens;Carcinoma;Cause of Death;CD3 Antigens;CD8B1 gene;Cells;checkpoint therapy;chemokine;chemotherapy;Chromatin;Chromatin Remodeling Factor;Clinical;Clinical Trials;Clinical Trials Network;Complex;Data;Detection;Early Therapeutic-Clinical Trials Network;Enhancers;Enzymes;Epigenetic Process;epigenetic regulation;epigenetic therapy;Equilibrium;Eragrostis;Exposure to;Frequencies;Funding;Genes;Genetic Transcription;Genomics;Goals;histone demethylase;Histones;Human;Immune;immune activation;immune cell infiltrate;immune checkpoint;Immune Evasion;Immune response;Immune system;Immunotherapy;Impairment;improved;In Vitro;Infiltration;inhibitor;innovation;Interdisciplinary Study;Investigation;Investigational Therapies;Link;loss of function mutation;lymph nodes;Lymphocyte;Malignant neoplasm of urinary bladder;Malignant Neoplasms;Mediating;men;Molecular;mouse model;Mus;Mutation;Nature;novel therapeutic intervention;novel therapeutics;Organoids;Outcome;Pathologic;Pathway interactions;Patients;PD-1 inhibitors;pembrolizumab;Phase I/II Clinical Trial;Phase I/II Trial;Polycomb;Precision therapeutics;Production;Property;recruit;Recurrence;refractory cancer;Regulation;Regulatory T-Lymphocyte;Repression;Repressor Proteins;Research;Resistance;response;Risk Reduction;Role;Site;Smoking;Solid Neoplasm;Somatic Mutation;stemness;T-Cell Activation;T-Lymphocyte;therapy resistant;Trans-Activators;Transcriptional Regulation;Transitional Cell Carcinoma;Translating;treatment strategy;tumor;tumor microenvironment;Urothelium;Veterans;Work

PROJECT_TITLE: Epigenetic Regulation of Immune Evasion in Bladder Cancer


ORG_CITY: OMAHA

ORG_NAME: OMAHA VA  MEDICAL CENTER

ORG_STATE: NE

PHR: My major research focus addresses chronic inflammatory lung disease, and the impact that behavioral and environmental exposures play in the compromise of lung innate defense against pathologic lung infections and injury. Utilizing pre-clinical mouse models and a well-characterized human lung cell and tissue biobank, I collaborate closely with pulmonologists who practice at the VA to conduct relevant pre-clinical research that can be used to address chronic lung disease in Veterans. Additionally, we have an existing cohort of Veterans with rural/agricultural occupational exposures to conduct relevant studies to our service region. In doing so, we hope to translate our findings to improved treatment of Veterans with pneumonia, as well as the identification of a lung disease risk biomarker in those with alcohol use disorders.

PI_NAMEs: WYATT, TODD A (contact)

PROJECT_TERMS: Acetaldehyde;Address;adduct;Admission activity;Age;agricultural center;Agriculture;airway epithelium;airway inflammation;Alcohol abuse;Alcohol consumption;alcohol exposure;alcohol misuse;alcohol response;alcohol use disorder;Alcohols;Aldehydes;Animal Model;Animals;antimicrobial;Area;Award;Bacterial Infections;Behavioral;Binding;biobank;Biochemical;Biological Markers;career;Caring;Cells;Chronic;chronic inflammatory lung disease;Chronic lung disease;Chronic Obstructive Pulmonary Disease;Cigarette;cigarette smoke;Cilia;Clinical;cohort;Collaborations;Collecting Cell;Core Facility;Coronavirus spike protein;cost;COVID-19;Cyclic AMP-Dependent Protein Kinases;Death Rate;desensitization;Development;digital;disorder risk;Dust;Elderly;empowerment;Environment;Environmental Exposure;Epithelial Cells;experience;Exposure to;exposure to cigarette smoke;Extramural Activities;former smoker;Functional disorder;Funding;Future;graduate student;Grant;Health;Health Care Costs;Healthcare;Healthcare Systems;Heavy Drinking;Hospitals;Human;human old age (65+);Impairment;improved;Individual;Inflammation;Inflammatory;Injury;innovation;instrument;interest;Interleukin-10;Laboratories;Life;Lung;Lung Diseases;Lung infections;lung injury;lung repair;Lung Transplantation;Macrophage;Malondialdehyde;Manuscripts;Mediating;Medical center;Mentors;Methodology;microCT;Military Personnel;military trauma;military veteran;Modality;Molecular;Morbidity - disease rate;mortality;Motility;mouse model;Mucociliary Clearance;Natural Immunity;Nebraska;neutrophil;Occupational Exposure;Outcome;Output;pathogen;Pathologic;Peer Review;Physicians;Play;Pneumonia;pneumonia treatment;pre-clinical;pre-clinical research;Predisposition;Preventive care;programs;protein kinase C epsilon;Proteins;Pulmonary Surfactant-Associated Protein D;receptor function;Recording of previous events;Regulation;Research;Research Project Grants;Respiratory Syncytial Virus Infections;response;Risk;Role;Rural;Safety;Sampling;SARS-CoV-2 infection;SARS-CoV-2 pathogenesis;Savings;Science;Scientist;Seminal;service member;Services;sex;Smoke;Smoker;Smoking;Source;Substance abuse problem;surfactant;System;Therapeutic;Time;Tissues;TNF-alpha converting enzyme;Training;Translating;undergraduate student;Universities;Veterans;viral pandemic;Virus;Virus Diseases;Virus Receptors;Work

PROJECT_TITLE: BLR&D Research Career Scientist Application


NIH_SPENDING_CATS: Biotechnology;Cancer;Genetics

ORG_CITY: LA JOLLA

ORG_NAME: SCRIPPS RESEARCH INSTITUTE, THE

PHR: NARRATIVE MYC is a pivotal transcription factor involved in cellular proliferation that affects a plethora of cell activities, however, its disordered nature and complex biology have made it difficult to study. We have developed a novel 1538-well fluorescence-based high throughput assay specific for identifying MYC inhibitors. Utilizing this assay, we will screen the entire >665,000 Scripps Drug Discovery Library (SDDL) and validate hits to identify inhibitor scaffolds with the potential to become new probes and therapeutics.

PI_NAMEs: JANDA, KIM  (contact)

PROGRAM_OFFICER_NAME: FORRY, SUZANNE L

PROJECT_TERMS: acute toxicity;Affect;Affinity;Amino Acids;Animal Model;Apoptosis;Attenuated;Binding;Binding Proteins;Binding Sites;Biological Assay;Biology;Breast Cancer Model;California;cancer initiation;Cell division;cell growth;Cell Line;Cell model;Cell Proliferation;Cells;Cellular Assay;Chemicals;Chick Embryo;ChIP-seq;Competitive Binding;Complex;Development;dimer;Dimerization;Disease;DNA Binding;Dose;drug discovery;Drug Kinetics;drug-like compound;E-Box Elements;Effectiveness;efficacy evaluation;Ensure;Evaluation;Exhibits;experimental study;Fibroblasts;Florida;Fluorescence;Fluorescent Probes;Follow-Up Studies;Gatekeeping;Genetic Transcription;high throughput screening;Histologic;Human;Human Cell Line;improved;In Vitro;in vivo;inhibitor;Interferometry;Label;Libraries;Ligands;Light;Maintenance;Malignant Neoplasms;Medicine;Methods;MicroRNAs;Microsomes;Modeling;mutant;Mutation;MYC gene;Nature;non-Native;novel;Oncogenes;Oncogenic;Oncoproteins;Pharmaceutical Chemistry;pharmacokinetics and pharmacodynamics;Phenotype;Plasma;Plasma Proteins;pluripotency;Post-Translational Protein Processing;Prevalence;Process;programs;Property;Proteins;Regulation;Research;Resistance;Role;Running;scaffold;screening;Series;Site;Specificity;Surface Plasmon Resonance;Testing;Therapeutic;therapeutic target;Therapeutic Uses;Tissues;Toxic effect;Transcription Elongation;transcription factor;Transcription Initiation;Transistors;tumor;tumor growth;United States National Institutes of Health;Validation;Xenograft Model

PROJECT_TITLE: High-Throughput Screen for the Oncoprotein MYC

STUDY_SECTION_NAME: Special Emphasis Panel[ZRG1-BST-F(55)R]


PHR: This VA Merit application focuses on defining how the balance between two muscarinic receptor subtypes, M1R and M3R, governs the function of colon cancer stem cells, the ‘mother cells’ from which other colon cancer cells arise – colon cancer stem cells drive tumor spread and resistance to treatment. We will learn how the expression of M1R and M3R in colon cancer is regulated. Then, we will see how blocking these receptors selectively affects responses to chemotherapy and survival in human colon cancer cells, 3-dimensional organoids (tumoroids), and in an innovative animal model that mimics colon cancer progression in people. We believe the work proposed will advance our long-term goal of developing new, effective and safe treatments for invasive colon cancer, a disease with limited treatment options that comprises 10% of all cancers in U.S. Veterans.

PI_NAMEs: RAUFMAN, JEAN-PIERRE  (contact)

PROJECT_TERMS: 3' Untranslated Regions;3-Dimensional;advanced disease;Advanced Malignant Neoplasm;Affect;Animal Model;Animals;Attenuated;Automobile Driving;beta catenin;Binding Sites;Biological Assay;Biological Markers;Bioluminescence;cancer cell;cancer stem cell;Cell Culture Techniques;Cells;chemotherapy;CHRM1 gene;CHRM3 gene;Clinical Trials;Colon;colon cancer progression;colon cancer treatment;Colon Carcinoma;Colonic Neoplasms;Computer Analysis;Computer Models;Data;design;Diagnosis;Disease;drug repurposing;Equilibrium;established cell line;Event;Exonuclease;FDA approved;Fluorouracil;Genetic Transcription;Genomic DNA;Goals;Growth;Human;human disease;Immune checkpoint inhibitor;Immunotherapeutic agent;Immunotherapy;In Vitro;in vivo;in vivo Model;Incidence;Individual;inhibitor;innovation;Interstitial Collagenase;Intervention;intervention effect;Invaded;Investigation;Knowledge;Learning;Link;Luciferases;Lung;Malignant Neoplasms;Messenger RNA;MicroRNAs;Molecular;Mothers;mRNA Translation;Mus;Muscarinic Acetylcholine Receptor;Muscarinic M3 Receptor;Neoplasm Metastasis;Neoplasms;Neurons;novel;Organoids;overexpression;oxaliplatin;Pattern;Persons;Porifera;Post-Transcriptional Regulation;pre-clinical;prognostic;programmed cell death protein 1;promoter;Property;Prostate;receptor;Receptor Activation;receptor expression;Rectal Cancer;Regulation;Relapse;Reporter;Reporting;Research;resilience;Resistance;response;RNA;Role;Signal Transduction;stem cell differentiation;stem cell function;stem cell proliferation;Testing;Therapeutic;therapy resistant;Transfection;translational potential;Translations;treatment response;tumor;tumor growth;tumor progression;Untranslated Regions;Untranslated RNA;Veterans;Work;Xenograft Model;Xenograft procedure

PROJECT_TITLE: Muscarinic Receptors Regulate Colon Cancer Stem Cell Function and Invasiveness


ADMINISTERING_IC: DE

ED_INST_TYPE: SCHOOLS OF DENTISTRY/ORAL HYGN

IC_NAME: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH

NIH_SPENDING_CATS: Aging;Bioengineering;Biotechnology;Clinical Research;Dental, Oral, and Craniofacial Disease;Infectious Diseases;Microbiome;Prevention

ORG_CITY: PORTLAND

ORG_DEPT: DENTISTRY

ORG_NAME: OREGON HEALTH & SCIENCE UNIVERSITY

ORG_STATE: OR

PHR: With the huge numbers of esthetic direct dental composites restoration being placed every year in  the US, enhancements in their reliability and clinical longevity offer significant health care  benefits to the general public. The new polymer system we are developing will produce a restorative  with the capacity to prevent colonization of mouth surfaces with oral bacteria, and to preserve the  tooth collagen component by incorporating compounds capable of inhibiting the action of  collagen-degrading enzymes. In summary, this proposal targets host and bacterial enzymes to  minimize or eliminate degradation of biomaterials/tissue interfaces over time, resulting in  longer-lasting adhesive restorations, including direct composites and indirect crowns and bridges  bonded with resin cements/adhesives.

PI_NAMEs: PFEIFER, CARMEM S. (contact)

PROGRAM_OFFICER_NAME: LOPEZ, ORLANDO

PROJECT_TITLE: Novel polymeric materials with improved durability in the oral environment: tailoring responses to host and bacterial enzymes with anti-proteolytic and ecology-based antimicrobial approaches.


ADMINISTERING_IC: MD

ED_INST_TYPE: SCHOOLS OF ARTS AND SCIENCES

IC_NAME: NATIONAL INSTITUTE ON MINORITY HEALTH AND HEALTH DISPARITIES

NIH_SPENDING_CATS: Anxiety Disorders;Basic Behavioral and Social Science;Behavioral and Social Science;Brain Disorders;Clinical Research;Health Disparities Research;Health Disparities and Racial or Ethnic Minority Health Research;Mental Health;Post-Traumatic Stress Disorder (PTSD);Racial and Ethnic Minority Health Research;Social Determinants of Health

ORG_CITY: HOUSTON

ORG_DEPT: PSYCHOLOGY

ORG_NAME: UNIVERSITY OF HOUSTON

ORG_STATE: TX

PHR: PROJECT NARRATIVE The proposed study will collect longitudinal data from 400 undocumented Latinx immigrant adults seeking asylum in the U.S. to examine how trauma exposure at various stages— prior to, embedded in the asylum- seeking experience, and during their first year settling in the U.S.— concurrently and prospectively influences risk for posttraumatic distress and quality of life via the biological pathway of inflammation. Using state-of-the- art biomarkers and mixed methods, the proposed study will assess Latinx adults seeking asylum in the U.S. at the U.S./Mexico border and follow them for one year. We innovate by assessing how trauma exposure at various stages relates to disparities in health outcomes and probing new sources of potential trauma for migrants including family separation, detention, and migration experiences in Mexico. This is the first study to identify multi-domain, multi-level factors that promote resilience in this population at the biological level and therefore takes first steps towards the development of novel therapeutics to address disparities in posttraumatic distress and quality of life.

PI_NAMEs: VENTA, AMANDA CRISTINA (contact)

PROGRAM_OFFICER_NAME: BURNS, PAUL ANTHONY

PROJECT_TERMS: Address;Adult;Advocacy;Affect;Anti-Inflammatory Agents;Area;Award;Behavioral;Biological;Biological Markers;Biology;Collaborations;Communities;community partners;coping;Country;court;Cultural Backgrounds;cultural values;Data;Development;Discrimination;Disparity;Distress;Environment;ethnic discrimination;Event;experience;Extramural Activities;Family;follow-up;Fostering;Funding;Gills;Goals;Grant;Health;health disparity;health knowledge;Hearing;Home;Immigrant;Immigration;Immune;immune function;Immunologic Tests;Individual;Inflammation;Inflammatory;inflammatory marker;innovation;Interleukin-10;Interleukin-6;Intervention;Knowledge;Latinx;Link;longitudinal, prospective study;Mediating;Methods;Mexico;Migrant;migration;novel;novel therapeutics;Outcome;Participant;Pathway interactions;Policies;Population;post-traumatic stress;promote resilience;prospective;Public Health;Quality of life;Quality of Life Assessment;Questionnaires;recruit;Religiosity;Research Personnel;resilience;Resources;Risk;Sampling;Scientist;Shelter facility;Side;social culture;Social support;Source;Testing;tetrahydrobiopterin;Therapeutic;TNF gene;Trauma;trauma exposure;United States National Institutes of Health;Vulnerable Populations;Work

PROJECT_TITLE: Posttraumatic Distress and the Immigrant Experience:  Individual and Interpersonal Risk and Resilience across Domains of Influence

STUDY_SECTION: MESH

STUDY_SECTION_NAME: Biobehavioral Mechanisms of Emotion, Stress and Health Study Section[MESH]


ADMINISTERING_IC: AA

ED_INST_TYPE: SCH ALLIED HEALTH PROFESSIONS

IC_NAME: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

NIH_SPENDING_CATS: Alcoholism, Alcohol Use and Health;Chronic Liver Disease and Cirrhosis;Digestive Diseases;Liver Disease;Nutrition;Substance Misuse

ORG_CITY: GREENSBORO

ORG_DEPT: NUTRITION

ORG_NAME: UNIVERSITY OF NORTH CAROLINA GREENSBORO

ORG_STATE: NC

PHR: PROJECT NARRATIVE Alcoholic liver disease is a leading cause of morbidity and mortality with no effective therapies available. This renewal project is to investigate the mechanisms of how alcohol induces hepatic free fatty acid accumulation. The goal of this project is to explore novel molecular targets for therapeutic interventions.

PI_NAMEs: ZHOU, ZHANXIANG  (contact)

PROGRAM_OFFICER_NAME: GAO, PETER

PROJECT_TERMS: Acetaldehyde;Acyl Coenzyme A;Adipocytes;alcohol exposure;alcohol response;Alcoholic Liver Diseases;Alcohols;Arachidonate 15-Lipoxygenase;Arachidonic Acids;Aryl Hydrocarbon Receptor;aryl hydrocarbon receptor ligand;ASCL1 gene;Biochemical Reaction;Cell Death;Cells;Cirrhosis;Coenzyme A;Coenzyme A Ligases;Data;Defect;Deposition;Development;diacylglycerol O-acyltransferase;Diet therapy;dietary;Dietary Intervention;Disease;effective therapy;Eicosanoids;endoplasmic reticulum stress;Evaluation;Exhibits;Experimental Models;Fatty Acids;FDA approved;Functional disorder;Funding;Generations;Genetic Transcription;Goals;Gold;Grant;Hepatic;Hepatitis;Hepatocyte;Homeostasis;Impairment;In Vitro;in vivo;Inflammation Mediators;Intervention;Knock-out;Knowledge;Lecithin;Ligands;Link;lipid mediator;Lipids;lipine;Liver;liver injury;Mediating;Metabolic;Metabolic Pathway;Metabolism;Mitochondria;molecular targeted therapies;Morbidity - disease rate;mortality;mouse model;Mus;Nonesterified Fatty Acids;novel;overexpression;oxidation;Pathogenesis;Pathologic;Pathway interactions;peroxisome;Pharmaceutical Preparations;Phenotype;Play;Predisposition;preservation;prevent;problem drinker;Production;Protein Isoforms;Reporting;Research;Role;Severity of illness;Signal Pathway;Signal Transduction;Testing;Therapeutic;therapeutic development;Therapeutic Intervention;Triglycerides;United States;Very low density lipoprotein

PROJECT_TITLE: Lipotoxicity in Alcoholic Liver Disease

STUDY_SECTION: HBPP

STUDY_SECTION_NAME: Hepatobiliary Pathophysiology Study Section[HBPP]


ED_INST_TYPE: OVERALL MEDICAL

ORG_CITY: TYLER

ORG_NAME: UNIVERSITY OF TEXAS HLTH CTR AT TYLER

PHR: Project Narrative: The incidence of empyema has steadily increased over the last four decades, leading to an annual healthcare cost of over half a billion dollars in the United States. Patient mortality approaches 20% and increases further with co-morbidities. We will use liposomal carrier delivery of fibrinolysins combined with transthoracic ultrasound to increase the efficacy of intrapleural fibrinolytic therapy, allowing for use of lower doses with concomitant decreased bleeding risk.

PI_NAMEs: KLEGERMAN, MELVIN E;KOMISSAROV, ANDREY  (contact)

PROGRAM_OFFICER_NAME: VUGA, LOUIS J

PROJECT_TERMS: 3-Dimensional;Acute;Address;Affinity;Age;Animals;bench to bedside;Biochemical;Biophysics;Chemicals;Chest;Chronic;Clinical;Coagulation Process;commercialization;comorbidity;Complex;Complication;Data;Death Rate;design;Disease;Dose;Drug Kinetics;early phase clinical trial;effusion;Elderly;Empyema;Encapsulated;experience;Fibrin;Fibrinolysis;Formulation;Foundations;Frequencies;Functional disorder;Half-Life;Health Care Costs;Hemorrhage;Histologic;human old age (65+);Imaging Techniques;improved;improved outcome;In Vitro;Incidence;indexing;Injury;innovation;Intervention;liposomal delivery;liposome vector;Liposomes;Liquid substance;Macroglobulins;male;Measurement;Mechanics;Modeling;Molecular;mortality;nanomolar;novel;novel strategies;older patient;Operative Surgical Procedures;Oryctolagus cuniculus;Outcome;Patients;Pharmaceutical Preparations;Physiological;Plasma;Plasmin;Plasminogen;Plasminogen Activator;Plasminogen Activator Inhibitor 1;Pleural;Pneumonia;Probability;Regimen;Research;Resistance;Risk;risk mitigation;Sampling;Sepsis;sex;Site;Solid;sound;Streptococcus pneumoniae;success;targeted delivery;Technology;Testing;Therapeutic;therapy outcome;Thoracic Surgical Procedures;Thrombolytic Therapy;Tissues;Translational Research;Treatment Protocols;Ultrasonography;ultrasound;United States;Urokinase;X-Ray Computed Tomography

PROJECT_TITLE: Enhanced Delivery of Thrombolytic Carriers for Empyema

STUDY_SECTION: GDD

STUDY_SECTION_NAME: Gene and Drug Delivery Systems Study Section[GDD]


NIH_SPENDING_CATS: Cancer;Childhood Leukemia;Genetics;Hematology;Orphan Drug;Pediatric;Pediatric Cancer;Rare Diseases

ORG_CITY: CHAPEL HILL

ORG_NAME: UNIV OF NORTH CAROLINA CHAPEL HILL

PHR: PROJECT NARRARTIVE NSD2 is a potent oncoprotein that has been implicated as a therapeutic target for a variety of cancers and was found to be among the most frequently mutated genes across 1,000 pediatric cancer genomes. A study in pediatric acute lymphoblastic leukemia (ALL) cell lines and patient samples revealed a recurring NSD2 gain of function mutation, and NSD2 is thought to be the primary oncogenic driver of a translocation found in 15-20% of multiple myeloma patients. Consequently, we aim to apply medicinal chemistry, chemical biology, and cancer biology approaches to discover first-in-class NSD2 bifunctional degraders in order to better understand NSD2 cancer biology, to assess NSD2 preclinical target validity, and as potential therapeutic agents.

PI_NAMEs: JAMES, LINDSEY INGERMAN (contact)

PROGRAM_OFFICER_NAME: CHEN, WEIWEI

PROJECT_TERMS: acute lymphoblastic leukemia cell;Acute Lymphocytic Leukemia;Affinity;Binding;Biological Assay;Biology;Cancer Biology;Cancer cell line;cancer genome;cancer subtypes;cancer therapy;Cell Line;Cells;Cellular Assay;Chemicals;Childhood Acute Lymphocytic Leukemia;Chromosomes;Complex;Data;design;Development;drug discovery;Drug Targeting;Epigenetic Process;epigenetic regulation;epigenetic therapy;epigenome;Family;gain of function mutation;Gene Silencing;Genes;Genetic;Genetic Transcription;Goals;Hand;Hematopoietic Neoplasms;Histones;improved;In Vitro;inhibitor;insight;knock-down;Knowledge;Lead;Length;Ligands;Lysine;Malignant Childhood Neoplasm;Malignant Neoplasms;Mediating;member;meter;Multiple Myeloma;Mutate;Mutation;N-terminal;novel;Nuclear Receptors;Oncogenic;Oncology;Oncoproteins;overexpression;Pathogenesis;Patients;Permeability;Pharmaceutical Chemistry;Pharmacology;PHD Finger;Phenocopy;Play;pre-clinical;pre-clinical assessment;prevent;protein degradation;Proteins;PWWP Domain;Qualifying;Reader;Reagent;receptor;receptor binding;recruit;Recurrence;Reporting;Sampling;screening;SET Domain;small molecule;small molecule inhibitor;Structure;Technology;Tertiary Protein Structure;Testing;Therapeutic;Therapeutic Agents;therapeutic target;tumorigenesis;ubiquitin ligase;ubiquitin-protein ligase;Work

PROJECT_TITLE: DISCOVERY OF FIRST-IN-CLASS NSD2 DEGRADERS FOR CANCER THERAPY


ADMINISTERING_IC: HD

IC_NAME: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT

NIH_SPENDING_CATS: Contraception/Reproduction;Genetics;Maternal Health;Pediatric;Pregnancy;Stem Cell Research;Stem Cell Research - Induced Pluripotent Stem Cell;Stem Cell Research - Induced Pluripotent Stem Cell - Human;Stem Cell Research - Nonembryonic - Human;Women's Health Research

ORG_CITY: STANFORD

ORG_DEPT: GENETICS

ORG_NAME: STANFORD UNIVERSITY

PHR: Extracellular vesicles traffic between the placenta and the mother, altering maternal behavior, modulating maternal immunotolerance, and even accelerating maternal wound healing. The ERV family, IAP forms viral-like particles (VLPs) that are an overlooked class of extracellular vesicles. We suggest that these particles are a necessary source of fetal-maternal communication, cellular regulation and somatic mutation during placentation.

PI_NAMEs: BAKER, JULIE C (contact)

PROGRAM_OFFICER_NAME: GIRARDI, GUILLERMINA

PROJECT_TERMS: Acceleration;Binding;Binding Proteins;Biology;bisulfite sequencing;blastocyst;cell growth regulation;Cell membrane;Cell Physiology;Cell secretion;Cells;Clustered Regularly Interspaced Short Palindromic Repeats;Communication;Data;Decidua;Decidual Cell;Defect;Elements;Embryo;Embryology;Endogenous Retroviruses;Evolution;extracellular;extracellular vesicles;Family;fetal;Frequencies;gag Gene Products;Gene Expression Regulation;Generations;Genes;genetic approach;Genome;Genomics;Goals;Human;Immunity;imprint;in vivo;insight;Investigation;knock-down;Knock-out;Length;Location;Maternal Behavior;Maternal-Fetal Exchange;Mediating;Mothers;Mus;Mutagens;Mutation;myometrium;particle;Pattern;Placenta;Placentation;Pregnancy;Protein Family;protein function;Proteins;Regulation;Regulatory Element;Reporter;Research;Retrotransposition;RNA;Role;Signal Transduction;single cell ATAC-seq;small hairpin RNA;Somatic Mutation;Source;Testing;Tissues;Transcript;Transgenes;trophoblast stem cell;Viral;Viral Physiology;Viral Proteins;wound healing

PROJECT_TITLE: The role of the endogenous retroviral family, IAP, in placentation.

STUDY_SECTION: PN

STUDY_SECTION_NAME: Pregnancy and Neonatology Study Section[PN]