UM1DK078616

TOPMED OMICS OF TYPE 2 DIABETES AND QUANTITATIVE TRAITS - PROJECT SUMMARY/ABSTRACT TYPE 2 DIABETES CONTINUES TO SPREAD GLOBALLY DUE TO UNHEALTHY ENVIRONMENT INTERACTING WITH GENETICS. RECENT GENETIC DISCOVERIES OF >700 VARIANTS AT >400 LOCI ASSOCIATED WITH TYPE 2 DIABETES (T2D) AND ITS RELATED QUANTITATIVE TRAITS (QTS: FASTING GLUCOSE (FG), INSULIN (FI) AND HEMOGLOBIN A1C (A1C)) GIVE INSIGHT INTO NEW T2D PATHOBIOLOGY. HOWEVER, MOST DISCOVERIES HAVE BEEN IN WHITES; STUDIES IN MINORITY GROUPS DISPROPORTIONATELY AFFECTED BY T2D ARE NEEDED. ALSO, MOST ASSOCIATIONS ARE IN THE NON-CODING GENOME, INDICATING THAT WHOLE GENOME SEQUENCE (WGS) ANALYSIS IS NEEDED FOR FULL VARIANT AND EFFECTOR GENE CHARACTERIZATION. THE NHLBI TRANS-OMICS FOR PRECISION MEDICINE (TOPMED) STUDY INCLUDES WGS FROM 21,493 CASES OF PREVALENT T2D AND 63,541 CONTROLS FROM FIVE POPULATIONS (41,557 EURO, 23,203 AA, 16,213 LATINO, 2,867 ASIAN, 1,194 SAMOAN ADIPOSITY STUDY) FROM 28 COHORTS AND UP TO 54,407 NON-T2D INDIVIDUALS WITH FG, FI OR HBA1C, AS WELL AS AGE OF T2D ONSET, LEVEL OF GLYCEMIC CONTROL AND LONGITUDINAL FOLLOW-UP FOR INCIDENT T2D EVENTS. IN THIS PROJECT AIM 1 IS TO TEST WGS-WIDE IN FIVE ANCESTRY GROUPS FOR KNOWN AND NEW COMMON AND RARE VARIANTS ASSOCIATED T2D AND QTS. WE WILL CONDUCT ANALYSES IN THE NHLBI BIODATA CATALYST. REPLICATION OF NOVEL VARIANTS IS AVAILABLE IN >1 MILLION INDIVIDUALS OF DIVERSE ANCESTRY FROM SIX BIOBANKS WITH T2D (UKBB, BIOME, BIOVU, PARTNERS BB, REGARDS, MVP) WITH TOPMED-IMPUTED GENOMIC ARRAY DATA. FOR HEALTH TRANSLATION, WE WILL GROUP T2D GENETIC RISK VARIANTS INTO POLYGENIC RISK SCORES (PRSS) THAT PREDICT FUTURE T2D OR CHARACTERIZE SPECIFIC PHYSIOLOGICAL AXES, AND USE VARIANTS IN MENDELIAN RANDOMIZATION (MR) TESTS OF DISEASE CAUSALITY. NEXT, TOPMED HAS BLOOD OMIC MEASURES FROM FIVE ANCESTRY GROUPS THAT MAY ALSO IDENTIFY NOVEL BIOLOGICAL NETWORKS RELEVANT TO T2D PATHOBIOLOGY, INCLUDING WHOLE BLOOD DNA METHYLATION (MEASURED BY SEQUENCING OR MICROARRAYS, N=11,131), TRANSCRIPTOMICS (RNA-SEQ) (N=8,334), PROTEOMICS (SOMALOGIC APTAMERS OR OLINK PROTEOMICS, N=7,897) AND METABOLOMICS (LIQUID CHROMATOGRAPHY/MASS SPECTROSCOPY, N=11,631). IN AIM 2, WE WILL TEST OMIC SIGNATURES ASSOCIATED WITH T2D AND QTS INDIVIDUALLY AND IN MULTIDIMENSIONAL OMIC AND GENOMIC NETWORK MODELS OF THE PATHOBIOLOGY OF T2D. FINALLY, IN AIM 3 WE PLAN TO INTEGRATE TOPMED WGS AND OMIC RESULTS WITH BESPOKE CELL OR TISSUE-SPECIFIC (BETA CELL, ISLET, LIVER, FAT AND MUSCLE) OMIC AND EPIGENOMIC ANNOTATION (ATAC-SEQ, RNA-SEQ, HI-C, CHIP-SEQ) IN THE ACCELERATING MEDICINE PARTNERSHIP (AMP) T2D DIABETES EPIGENOME ATLAS, AND WITH HUNDREDS OF ADDITIONAL GENOMIC TRAIT ASSOCIATIONS IN THE AMP T2D KNOWLEDGE PORTAL (T2DKP) FOR ‘IN SILICO VARIANT-TO-FUNCTION’ AND PHENOMIC STUDIES. COMPLETE FUNCTIONAL MAPPING WITH BLOOD AND TISSUE-SPECIFIC OMIC INTEGRATION OF THE HUMAN T2D AND QT GENOME IS ON THE HORIZON. OUR MULTIDISCIPLINARY, MULTICENTER TEAM HAS A PROVEN TRACK RECORD IN GENETICS AND OMIC DISCOVERY. WE ARE ACTIVELY WORKING WITH TOPMED, AMP T2D DGA AND T2DKP DATA. WE ARE WELL POSITIONED TO ACHIEVE THE AIMS OF THE PROPOSAL, WITH THE INTENTION TO FIND NEW APPROACHES TO ADDRESS THE GLOBAL EPIDEMIC OF T2D IN ALL POPULATIONS AT RISK.

The General Hospital Corporation

(1) TO PROMOTE EXTRAMURAL BASIC AND CLINICAL BIOMEDICAL RESEARCH THAT IMPROVES THE UNDERSTANDING OF THE MECHANISMS UNDERLYING DISEASE AND LEADS TO IMPROVED PREVENTIONS, DIAGNOSIS, AND TREATMENT OF DIABETES, DIGESTIVE, AND KIDNEY DISEASES. PROGRAMMATIC AREAS WITHIN THE NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES INCLUDE DIABETES, DIGESTIVE, ENDOCRINE, HEMATOLOGIC, LIVER, METABOLIC, NEPHROLOGIC, NUTRITION, OBESITY, AND UROLOGIC DISEASES. SPECIFIC PROGRAMS AREAS OF INTEREST INCLUDE THE FOLLOWING: (A) FOR DIABETES, ENDOCRINE, AND METABOLIC DISEASES AREAS: FUNDAMENTAL AND CLINICAL STUDIES INCLUDING THE ETIOLOGY, PATHOGENESIS, PREVENTION, DIAGNOSIS, TREATMENT AND CURE OF DIABETES MELLITUS AND ITS COMPLICATIONS, NORMAL AND ABNORMAL FUNCTION OF THE PITUITARY, THYROID, PARATHYROID, ADRENAL, AND OTHER HORMONE SECRETING GLANDS, HORMONAL REGULATION OF BONE, ADIPOSE TISSUE, AND LIVER, ON FUNDAMENTAL ASPECTS OF SIGNAL TRANSDUCTION, INCLUDING THE ACTION OF HORMONES, COREGULATORS, AND CHROMATIN REMODELING PROTEINS, HORMONE BIOSYNTHESIS, SECRETION, METABOLISM, AND BINDING, AND ON HORMONAL REGULATION OF GENE EXPRESSION AND THE ROLE(S) OF SELECTIVE RECEPTOR MODULATORS AS PARTIAL AGONISTS OR ANTAGONISTS OF HORMONE ACTION, AND FUNDAMENTAL STUDIES RELEVANT TO METABOLIC DISORDERS INCLUDING MEMBRANE STRUCTURE, FUNCTION, AND TRANSPORT PHENOMENA AND ENZYME BIOSYNTHESIS, AND BASIC AND CLINICAL STUDIES ON THE ETIOLOGY, PATHOGENESIS, PREVENTION, AND TREATMENT OF INHERITED METABOLIC DISORDERS (SUCH AS CYSTIC FIBROSIS). (B) FOR DIGESTIVE DISEASE AND NUTRITION AREAS: GENETICS AND GENOMICS OF THE GI TRACT AND ITS DISEASES, GENETICS AND GENOMICS OF LIVER/PANCREAS AND DISEASES, GENETICS AND GENOMICS OF NUTRITION, GENETICS AND GENOMICS OF OBESITY, BARIATRIC SURGERY, CLINICAL NUTRITION RESEARCH, CLINICAL OBESITY RESEARCH, COMPLICATIONS OF CHRONIC LIVER DISEASE, FATTY LIVER DISEASE, GENETIC LIVER DISEASE, HIV AND LIVER, CELL INJURY, REPAIR, FIBROSIS AND INFLAMMATION IN THE LIVER, LIVER CANCER, LIVER TRANSPLANTATION, PEDIATRIC LIVER DISEASE, VIRAL HEPATITIS AND INFECTIOUS DISEASES, GASTROINTESTINAL AND NUTRITION EFFECTS OF AIDS, GASTROINTESTINAL MUCOSAL AND IMMUNOLOGY, GASTROINTESTINAL MOTILITY, BASIC NEUROGASTROENTEROLOGY, GASTROINTESTINAL DEVELOPMENT, GASTROINTESTINAL EPITHELIAL BIOLOGY, GASTROINTESTINAL INFLAMMATION, DIGESTIVE DISEASES EPIDEMIOLOGY AND DATA SYSTEMS, NUTRITIONAL EPIDEMIOLOGY AND DATA SYSTEMS, AUTOIMMUNE LIVER DISEASE, BILE, BILIRUBIN AND CHOLESTASIS, BIOENGINEERING AND BIOTECHNOLOGY RELATED TO DIGESTIVE DISEASES, LIVER, NUTRITION AND OBESITY, CELL AND MOLECULAR BIOLOGY OF THE LIVER, DEVELOPMENTAL BIOLOGY AND REGENERATION, DRUG-INDUCED LIVER DISEASE, GALLBLADDER DISEASE AND BILIARY DISEASES, EXOCRINE PANCREAS BIOLOGY AND DISEASES, GASTROINTESTINAL NEUROENDOCRINOLOGY, GASTROINTESTINAL TRANSPORT AND ABSORPTION, NUTRIENT METABOLISM, PEDIATRIC CLINICAL OBESITY, CLINICAL TRIALS IN DIGESTIVE DISEASES, LIVER CLINICAL TRIALS, OBESITY PREVENTION AND TREATMENT, AND OBESITY AND EATING DISORDERS. (C) FOR KIDNEY, UROLOGIC AND HEMATOLOGIC DISEASES AREAS: STUDIES OF THE DEVELOPMENT, PHYSIOLOGY, AND CELL BIOLOGY OF THE KIDNEY, PATHOPHYSIOLOGY OF THE KIDNEY, GENETICS OF KIDNEY DISORDERS, IMMUNE MECHANISMS OF KIDNEY DISEASE, KIDNEY DISEASE AS A COMPLICATION OF DIABETES, EFFECTS OF DRUGS, NEPHROTOXINS AND ENVIRONMENTAL TOXINS ON THE KIDNEY, MECHANISMS OF KIDNEY INJURY REPAIR, IMPROVED DIAGNOSIS, PREVENTION AND TREATMENT OF CHRONIC KIDNEY DISEASE AND END-STAGE RENAL DISEASE, IMPROVED APPROACHES TO MAINTENANCE DIALYSIS THERAPIES, BASIC STUDIES OF LOWER URINARY TRACT CELL BIOLOGY, DEVELOPMENT, PHYSIOLOGY, AND PATHOPHYSIOLOGY, CLINICAL STUDIES OF BLADDER DYSFUNCTION, INCONTINENCE, PYELONEPHRITIS, INTERSTITIAL CYSTITIS, BENIGN PROSTATIC HYPERPLASIA, UROLITHIASIS, AND VESICOURETERAL REFLUX, DEVELOPMENT OF NOVEL DIAGNOSTIC TOOLS AND IMPROVED THERAPIES, INCLUDING TISSUE ENGINEERING STRATEGIES, FOR UROLOGIC DISORDERS,RESEARCH ON HEMATOPOIETIC CELL DIFFERENTIATION, METABOLISM OF IRON OVERLOAD AND DEFICIENCY, STRUCTURE, BIOSYNTHESIS AND GENETIC REGULATION OF HEMOGLOBIN, AS WELL AS RESEARCH ON THE ETIOLOGY, PATHOGENESIS, AND THERAPEUTIC MODALITIES FOR THE ANEMIA OF INFLAMMATION AND CHRONIC DISEASES. (2) TO ENCOURAGE BASIC AND CLINICAL RESEARCH TRAINING AND CAREER DEVELOPMENT OF SCIENTISTS DURING THE EARLY STAGES OF THEIR CAREERS. THE RUTH L. KIRSCHSTEIN NATIONAL RESEARCH SERVICE AWARD (NRSA) FUNDS BASIC AND CLINICAL RESEARCH TRAINING, SUPPORT FOR CAREER DEVELOPMENT, AND THE TRANSITION FROM POSTDOCTORAL BIOMEDICAL RESEARCH TRAINING TO INDEPENDENT RESEARCH RELATED TO DIABETES, DIGESTIVE, ENDOCRINE, HEMATOLOGIC, LIVER, METABOLIC, NEPHROLOGIC, NUTRITION, OBESITY, AND UROLOGIC DISEASES. (3) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM. THE SBIR PROGRAM AIMS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO ENHANCE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. (4) TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM. THE STTR PROGRAM INTENDS TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.847 - Diabetes, Digestive, and Kidney Diseases Extramural Research

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [HHS - NIH]

Massachusetts United States

State-Wide

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the total obligations have increased 319% from $902,027 to $3,776,636.