R01DK139157

ROLE OF LIPOGENIC PATHWAYS IN INTESTINAL REMODELING AFTER GASTRIC BYPASS SURGERY - PROJECT SUMMARY THE RISING INCIDENCE OF TYPE 2 DIABETES (T2D) HIGHLIGHTS A GROWING NEED TO UNDERSTAND MECHANISMS BEHIND HIGHLY-EFFECTIVE THERAPIES SUCH AS ROUX-EN-Y GASTRIC BYPASS SURGERY (RYGB) IN ORDER TO DEVELOP BETTER, MORE WIDELY-APPLICABLE TREATMENTS. ADAPTATION IN THE JEJUNUM (ROUX LIMB) IS A HYPOTHESIZED CONTRIBUTOR TO DIABETES IMPROVEMENT AFTER RYGB, AND THIS IS SUPPORTED BY OUR LAB’S WORK DEMONSTRATING A RELATIONSHIP OF JEJUNAL ADAPTATION WITH BOTH GLYCEMIC CONTROL AND T2D REMISSION IN HUMANS. OUR LONG-TERM GOAL IS TO UNDERSTAND HOW CHANGES IN GI ANATOMY EFFECT THE POWERFUL, DURABLE SHIFT IN ENERGY HOMEOSTASIS OBSERVED AFTER BARIATRIC SURGERY. THE OVERALL OBJECTIVE OF THIS APPLICATION IS TO UNDERSTAND HOW CHANGES IN GI ANATOMY ELICIT THE POWERFUL, DURABLE SHIFT IN ENERGY HOMEOSTASIS OBSERVED AFTER BARIATRIC SURGERY. OUR PRELIMINARY DATA DEMONSTRATE SEGMENT-SPECIFIC ACTIVATION OF LXR SIGNALING IN ROUX LIMB OF MICE AND HUMANS AFTER RYGB WHICH IS LOST IN HUMANS WITHOUT T2D REMISSION, AS WELL AS DOWNREGULATION OF PPARA SIGNALING AND ENRICHMENT OF LIPIDS, ESPECIALLY PLASMA MEMBRANE LIPIDS, IN ROUX LIMB. THE CENTRAL HYPOTHESIS IS THAT THAT ALTERATION IN INTESTINAL EPITHELIAL LIPID HOMEOSTASIS, DRIVEN BY LXR AND PPARA SIGNALING, IS NECESSARY FOR RL ADAPTATION AND ASSOCIATED IMPROVEMENTS IN GLUCOSE HOMEOSTASIS AFTER RYGB. THE RATIONALE FOR THIS PROJECT IS THAT DE NOVO LIPOGENESIS COULD BE A PATHWAY FOR LOCAL INTESTINAL GLUCOSE UTILIZATION, WHICH IS SUPPORTED BY OUR PRELIMINARY DATA. THESE EXPERIMENTS WILL ALLOW US TO DIRECTLY TEST THE ROLE FOR LIPOGENIC PATHWAYS TO CONTRIBUTE TO INTESTINAL ADAPTATION AND METABOLIC HOMEOSTASIS MORE BROADLY. THE CENTRAL HYPOTHESIS WILL BE TESTED IN TWO SPECIFIC AIMS: (1) TO TEST THE HYPOTHESIS THAT LXR- AND PPARA- MEDIATED LIPOGENESIS DRIVES RL ADAPTATION AND GLUCOSE REGULATION IN DIET-INDUCED OBESITY; AND (2) TO TEST THE HYPOTHESIS THAT CHANGES IN LIPOGENESIS DRIVE INTESTINAL EPITHELIAL ADAPTATION IN A DISEASE-RELEVANT IN VITRO MODEL SYSTEM. WE WILL USE MOUSE MODELS INCLUDING OUR MURINE MODEL OF BARIATRIC SURGERY IN AIM 1; AIM 2 WILL USE A JEJUNAL ORGANOID MODEL DERIVED FROM HUMAN PATIENTS WITH OBESITY, WHO ARE UNDERGOING BARIATRIC SURGERY. THIS PROJECT WILL SHED LIGHT ON THE KEY INTESTINAL EPITHELIAL CELLS RESPONSIBLE FOR ROUX LIMB ADAPTATION AND ULTIMATELY, POTENTIAL DRUG TARGETS THAT COULD MIMIC THE BENEFICIAL EFFECTS OF RYGB.

Children's 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

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)