R01DK144425

HARNESSING NOVEL HUMAN ENDOCRINE PROGENITOR BIOLOGY FOR ENHANCED GENERATION OF BETA CELLS FROM STEM CELLS - THE LONG-TERM OBJECTIVES OF THIS PROJECT ARE TO ELUCIDATE THE MECHANISMS UNDERLYING HUMAN ENDOCRINE LINEAGE COMMITMENT AND HARNESS THIS KNOWLEDGE TO IMPROVE STRATEGIES FOR BETA CELL REPLACEMENT IN DIABETES TREATMENT. DIABETES IS ONE OF THE FASTEST GROWING HEALTH EMERGENCIES WORLDWIDE, AFFECTING HUNDREDS OF MILLIONS OF INDIVIDUALS. TYPE 1 DIABETES (T1D) IS A DISEASE OF THE ENDOCRINE PANCREAS CHARACTERIZED BY LACK OF GLUCOSE HOMEOSTASIS DUE TO IMMUNE-MEDIATED DESTRUCTION OF INSULIN-PRODUCING BETA CELLS. BETA CELL REPLACEMENT THERAPY HOLDS GREAT PROMISE FOR ELIMINATING THE NEED FOR EXOGENOUS INSULIN DELIVERY AND EFFECTIVELY CURING THE DISEASE. UNDERSTANDING THE MECHANISMS UNDERLYING ENDOCRINE CELL FATE AND FUNCTION WILL BE CRUCIAL FOR CONTINUED PROGRESS TOWARDS REALIZING THE GOALS OF BOTH CELL REPLACEMENT THERAPY AND BETA CELL REGENERATION. ALTHOUGH SEVERAL PROTOCOLS HAVE BEEN DEVISED TO GENERATE INSULIN-SECRETING BETA-LIKE CELLS FROM HUMAN PLURIPOTENT STEM CELLS (HPSCS), THESE PROTOCOLS SUFFER FROM THE PRODUCTION OF NON- ENDOCRINE CELL TYPES AND A FAILURE TO MATCH THE TRANSCRIPTIONAL PROFILES AND GLUCOSE RESPONSIVENESS OF NATIVE ADULT HUMAN ISLETS. THIS MAY BE BECAUSE CURRENT PROTOCOLS ARE BASED ON KNOWLEDGE OF RODENT DEVELOPMENT AND MAY THEREFORE BE MISSING KEY REGULATORY PATHWAYS AND LINEAGE STEPS UNIQUE TO HUMAN DEVELOPMENT. INDEED, MULTIPLE STUDIES HAVE IDENTIFIED DISCREPANCIES BETWEEN MOUSE AND HUMAN PANCREATIC ISLETS, INCLUDING STRUCTURAL, TRANSCRIPTOMIC, AND METABOLIC DIFFERENCES. THEREFORE, GAINING A DEEPER UNDERSTANDING OF HUMAN ENDOCRINE DEVELOPMENT IS CRUCIAL FOR CONTINUED PROGRESS TOWARDS GENERATING IN VITRO-DERIVED BETA CELLS THAT RECAPITULATE ENDOGENOUS FUNCTION. OUR LABORATORY HAS RECENTLY MADE A SET OF FUNDAMENTAL DISCOVERIES REGARDING ENDOCRINE PROGENITORS (EPS) IN HUMAN. WE UTILIZED SINGLE-CELL MULTI-OMICS TO GENERATE A COMPREHENSIVE ATLAS OF DEVELOPING PANCREAS, IDENTIFIED FOUR NOVEL EP STATES UNIQUE TO HUMAN, AND REVEALED DIVERGENT LINEAGE RELATIONSHIPS IN HUMAN TISSUE VERSUS MOUSE. WE HAVE IDENTIFIED A NOVEL CELL POPULATION, MARKED BY THE TRANSCRIPTION FACTOR FEV, THAT REPRESENTS A FATE-RESTRICTED EP POPULATION THAT GIVES RISE TO HUMAN BETA CELLS. OUR WORK NOW PROVIDES A CRITICAL NEW LENS THROUGH WHICH TO EXAMINE HUMAN ENDOCRINE LINEAGE COMMITMENT, AND TO APPLY THIS KNOWLEDGE TO IMPROVE BETA CELL DIFFERENTIATION FROM HPSCS. OUR GOAL IS TO ELUCIDATE THE MECHANISMS UNDERLYING HUMAN ENDOCRINE LINEAGE COMMITMENT AND HARNESS THIS KNOWLEDGE TO IMPROVE STRATEGIES FOR BETA CELL REPLACEMENT. THE EXPERIMENTS OUTLINED IN THIS PROPOSAL BEGIN WITH A FOCUS ON CHARACTERIZING THE SPATIAL AND TEMPORAL APPEARANCE OF THE NOVEL EP POPULATIONS THAT WE HAVE IDENTIFIED IN DEVELOPING HUMAN PANCREAS. IN ADDITION, STUDIES WILL BE UNDERTAKEN TO INVESTIGATE THE FUNCTION OF THE GENE FEV IN THE DEVELOPMENT OF HUMAN BETA CELLS USING GENOME EDITING OF HPSC-DERIVED ENDOCRINE CELLS. LASTLY, WE WILL USE A COMBINATION OF STRATEGIES TO ISOLATE DISTINCT POPULATIONS OF DIFFERENTIATING HPSC-DERIVED BETA-LIKE CELLS AND THEIR PROGENITORS TO TEST WHETHER OFF-TARGET CELLS ARE DETRIMENTAL AND TO REFINE WHICH SUB-POPULATION LEADS TO OPTIMAL DIABETIC RESCUE.

San Francisco Regents Of The University Of California

(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]

San Francisco, California 94143 United States

Single Zip Code

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