R01DK142433

MITOPROTECTIVE THERAPIES FOR KIDNEY INJURY - ABSTRACT ACUTE KIDNEY INJURY (AKI) IS A COMMON DISEASE THAT IS ASSOCIATED WITH ADVERSE SHORT AND LONG-TERM SEQUELAE. AKI USUALLY OCCURS IN HOSPITALIZED PATIENTS AND IN THE SETTINGS OF OTHER CLINICAL CONDITIONS, SUCH AS SEPSIS, RHABDOMYOLYSIS, AND CARDIOVASCULAR AND ONCOLOGICAL DISEASES, WHERE THE UNDERLYING DISEASE AND OR ASSOCIATED THERAPEUTIC INTERVENTION CAUSES ABRUPT LOSS OF RENAL FUNCTION. WHILE THE CAUSAL MECHANISMS ARE INCOMPLETELY UNDERSTOOD, RENAL TUBULAR EPITHELIAL CELL (RTEC) DYSFUNCTION AND CELL DEATH IS THE PATHOLOGICAL LESION THAT INITIATES AND TRIGGERS AKI. IMPORTANTLY, IT HAS NOW BEEN ESTABLISHED THAT DISRUPTION OF MITOCHONDRIAL HOMEOSTASIS IN THE EARLY STAGES OF ACUTE KIDNEY INJURY DRIVES SUBSEQUENT RTEC CELL DEATH AND AKI. PHARMACOLOGICAL INTERVENTIONS THAT STABILIZE MITOCHONDRIAL FUNCTION COULD THUS MITIGATE AKI AND OR AUGMENT RECOVERY, HOWEVER, MITOCHONDRIA- LOCALIZED DRUGGABLE TARGETS HAVE REMAINED ELUSIVE. UTILIZING UNBIASED FUNCTIONAL GENOMIC AND CHEMICAL GENETIC SCREENS, HERE, WE HAVE IDENTIFIED A MITOCHONDRIA-LOCALIZED DRUGGABLE PROTEIN PHOSPHOLIPID SCRAMBLASE 3 (PLSCR3) AS A BIOLOGICAL TARGET OF MITOPROTECTIVE TETRA-PEPTIDE DRUG SS-31. OUR PRELIMINARY STUDIES USING COMPLEMENTARY PHARMACOLOGICAL AND GENETIC APPROACHES DEMONSTRATE THAT ACTIVATION OF PLSCR3 STABILIZES MITOCHONDRIAL FUNCTION, REDUCES RTEC CELL DEATH, AND MITIGATES AKI. FURTHERMORE, WE HAVE IDENTIFIED NOVEL ORALLY BIO-AVAILABLE SMALL-MOLECULE ACTIVATORS OF THIS MITOCHONDRIAL PROTEIN. IN THE CURRENT APPLICATION, WE PROPOSE TO UTILIZE GENETIC, BIOCHEMICAL, CELL BIOLOGY, PHARMACOKINETICS, AND PHARMACOLOGICAL APPROACHES TO CHARACTERIZE THIS NOVEL ACTIVATOR. WE HYPOTHESIZE THAT PHARMACOLOGICAL AUGMENTATION OF PLSCR3 FUNCTION THROUGH A NOVEL AGONIST (AB-3) OR TRANSCRIPTIONAL UPREGULATION (BELUMOSUDIL, AN FDA-APPROVED ROCK2 KINASE INHIBITOR) WOULD ALLEVIATE MITOCHONDRIAL DYSFUNCTION, TEC DEATH, AND AKI. TO TEST OUR HYPOTHESIS AND ACCOMPLISH THE OBJECTIVE OF DEVELOPING NEW MITOCHONDRIAL-TARGETED AKI THERAPEUTICS, WE PLAN TO: (A) DETERMINE TARGET SPECIFICITY, PHARMACOLOGICAL PROPERTIES, IN VIVO PHARMACOKINETICS OF AB-3 AND BELUMOSUDIL IN MICE AND PIGS AND (B) DETERMINE THE EFFICACY OF AB-3 AND BELUMOSUDIL IN ISCHEMIA-REPERFUSION (I/R), CISPLATIN NEPHROTOXICITY, AND RHABDOMYOLYSIS ASSOCIATED MURINE MODELS OF AKI ALONG WITH I/R PORCINE MODEL OF AKI. THE PROPOSED RESEARCH IS HIGHLY SIGNIFICANT BECAUSE, AT THE END OF THE PROJECT, WE EXPECT TO IDENTIFY A SMALL MOLECULE ACTIVATOR WITH A DEFINED MECHANISM OF ACTION AND NOVEL MITOCHONDRIAL STABILIZING ACTIVITY. OUR PROPOSED STUDIES WILL PROVIDE COMPELLING PROOF-OF-PRINCIPLE DATA REINFORCING THE GROUNDWORK FOR THE DEVELOPMENT AND SUBSEQUENT ASSESSMENT OF TWO CLASSES OF PHARMACOLOGICAL COMPOUNDS THAT EITHER ACTIVATE (AB-3) OR UPREGULATE (BELUMOSUDIL) PLSCR3 AS A THERAPEUTIC APPROACH FOR MITIGATING AKI.

University Of Tennessee

(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]

Memphis, Tennessee 38163 United States

Single Zip Code

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