R01DK141594

MITOCHONDRIAL DYSFUNCTION DRIVEN BY SPLICING FACTOR MUTATIONS IN MDS - PROJECT SUMMARY MYELODYSPLASTIC SYNDROME (MDS) IS CHARACTERIZED BY CLONAL EXPANSION OF DYSPLASTIC HEMATOPOIETIC CELLS AND REDUCTION IN CIRCULATING WHITE BLOOD CELLS, RED BLOOD CELLS, AND PLATELETS. SPLICING FACTOR MUTATIONS ARE THE MOST COMMON DRIVER MUTATIONS IN MDS. WE HAVE IDENTIFIED A NEW MECHANISM OF MITOCHONDRIAL QUALITY CONTROL THAT IS ESSENTIAL FOR CELL SURVIVAL IN MDS CAUSED BY MUTATIONS IN THE SPLICING FACTOR SRSF2. TARGETING THIS PATHWAY IS LETHAL TO SRSF2 MUTANT CELLS, SUGGESTING A THERAPEUTIC APPROACH FOR MDS DRIVEN BY SPLICING FACTOR MUTATIONS. DYSFUNCTIONAL MITOCHONDRIA ARE TARGETED FOR LYSOSOMAL DEGRADATION THROUGH A PATHWAY TERMED MITOPHAGY, WHICH IS ACTIVATED BY THE PROTEIN KINASE PINK1. WE HAVE FOUND THAT MITOCHONDRIAL DYSFUNCTION ENHANCES THE SPLICING, STABILITY, AND ABUNDANCE OF PINK1 MRNA TO SUPPORT AN INCREASED DEMAND FOR MITOPHAGY. THIS MECHANISM IS ESSENTIAL FOR THE SURVIVAL OF CELLS FROM MDS PATIENTS WITH THE SRSF2P95H/+ MUTATION, WHICH IS ASSOCIATED WITH HIGH GRADE MDS AND THERAPY RESISTANCE. WE SHOW THAT THE SRSF2P95H MUTATION ALTERS SPLICING OF NUCLEAR-ENCODED MITOCHONDRIAL GENES AND IMPAIRS OXIDATIVE PHOSPHORYLATION. THIS MITOCHONDRIAL DYSFUNCTION THEN SIGNALS IN A RETROGRADE MANNER TO THE NUCLEUS TO ENHANCE PINK1 SPLICING. INHIBITION OF THE SPLICING REGULATOR GLYCOGEN SYNTHASE KINASE 3 (GSK-3) IMPAIRS PINK1 SPLICING, REDUCES MITOPHAGY, AND IS LETHAL TO SRSF2 MUTANT CELLS. FURTHERMORE, MDS AND AML PATIENTS WITH SRSF2 MUTATIONS IN THE CANCER GENOME ATLAS EXPRESS ROBUSTLY HIGHER LEVELS OF MITOPHAGY GENES THAN PATIENTS WITH WILD-TYPE SRSF2, INDICATING THAT INCREASED MITOPHAGY IS A COMMON FEATURE OF SRSF2 MUTANT MDS. WE THEREFORE PROPOSE THAT MITOCHONDRIAL DYSFUNCTION ENHANCES PINK1 SPLICING TO ALLOW INCREASED MITOPHAGY AND THAT SRSF2P95H/+ ACTIVATES THIS PATHWAY INDIRECTLY BY DISRUPTING OXIDATIVE PHOSPHORYLATION. INHIBITION OF PINK1 SPLICING WITH GSK-3 INHIBITORS IS LETHAL TO SRSF2 MUTANT CELLS, SUGGESTING A THERAPEUTIC APPROACH FOR MDS DRIVEN BY RECURRENT MUTATIONS IN SRSF2. OUR SPECIFIC AIMS ARE TO: 1) ADDRESS GENETICALLY HOW IMPAIRED OXIDATIVE PHOSPHORYLATION ALTERS PINK1 SPLICING USING A SERIES OF PATIENT-DERIVED MITOCHONDRIAL DNA MUTATIONS THAT DISRUPT OXIDATIVE PHOSPHORYLATION, 2) APPLY LONG-READ RNA-SEQUENCING TO IDENTIFY FULL LENGTH TRANSCRIPTS WHOSE SPLICING IS ALTERED BY THE SRSF2P95H MUTATION AND, MORE GENERALLY, ALTERED BY MITOCHONDRIAL DYSFUNCTION, AND 3) EXPLORE A NEW MECHANISM FOR MITOCHONDRIAL SURVEILLANCE THROUGH ALTERNATIVE SPLICING OF PINK1.

Trustees Of The University Of Pennsylvania

(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]

Pennsylvania United States

State-Wide

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