R01DK129793

IMPACT OF METABOLIC ACIDOSIS ON MUSCLE MITOCHONDRIAL ENERGETICS, METABOLIC HEALTH, AND PHYSICAL ENDURANCE IN PERSONS WITH CHRONIC KIDNEY DISEASE - PROJECT SUMMARY AND ABSTRACT

CHRONIC KIDNEY DISEASE (CKD) IS HIGHLY PREVALENT, AFFECTING 14% OF THE U.S. POPULATION, LEADING TO SUBSTANTIAL MORBIDITY AND REDUCED QUALITY OF LIFE. OLDER ADULTS WITH CKD IDENTIFY MAINTENANCE OF FUNCTIONAL INDEPENDENCE AS THEIR TOP PRIORITY.

SKELETAL MUSCLE HEALTH IS CRITICAL FOR MOBILITY AND AN UNDERRECOGNIZED TARGET OF METABOLIC ACIDOSIS (MA) AND PROTEIN ENERGY WASTING IN CKD. SKELETAL MUSCLE ENDURANCE PROVIDES A WINDOW INTO MUSCLE METABOLIC HEALTH AND MUSCLE QUALITY.

MUSCLE MITOCHONDRIAL METABOLISM IS CENTRAL TO MUSCLE AND WALKING ENDURANCE, PROVIDING ENERGY FROM CARBOHYDRATES AND FATS TO POWER REPEATED MUSCLE CONTRACTION. WE SHOWED METABOLIC ACIDOSIS AND MUSCLE ADIPOSITY AS THE MAJOR DETERMINANTS OF MUSCLE MITOCHONDRIAL FUNCTION.

METABOLIC ACIDOSIS (MA) IS LONG BELIEVED TO BE THE MAIN MECHANISM LEADING TO SKELETAL MUSCLE WASTING AND PERIPHERAL INSULIN RESISTANCE IN CKD. SKELETAL MUSCLE MITOCHONDRIAL METABOLISM IS CONSIDERED A PRINCIPAL DETERMINANT OF PERIPHERAL INSULIN SENSITIVITY AND MUSCLE QUALITY, BUT LITTLE IS KNOWN OF THE IMPACT OF MA ON MUSCLE MITOCHONDRIAL FUNCTION.

MUSCLE MITOCHONDRIAL DYSFUNCTION LEADS TO DEFECTIVE LIPID METABOLISM, AUGMENTING ADIPOSITY AND LIPOTOXIC INTERMEDIATES RESULTING IN INSULIN RESISTANCE, LOW ENDURANCE, AND MUSCLE ATROPHY. USING IN VIVO 31PHOSPHORUS MAGNETIC RESONANCE SPECTROSCOPY (31P MRS), WE SHOWED THAT THE PRESENCE AND SEVERITY OF CKD IS STRONGLY ASSOCIATED WITH IMPAIRED MUSCLE MITOCHONDRIAL CAPACITY TO GENERATE ATP, TRANSLATING INTO POOR WALKING ENDURANCE. WE ALSO SHOWED MA AND MUSCLE ADIPOSITY ARE THE MAJOR DETERMINANTS OF MUSCLE MITOCHONDRIAL FUNCTION.

RECENTLY, A NON-SODIUM POLYMER (VEVERIMER) SELECTIVELY BINDING HYDROGEN CHLORIDE IN THE GASTROINTESTINAL TRACT SAFELY IMPROVED SERUM BICARBONATE AND MEANINGFULLY IMPROVED PHYSICAL FUNCTIONING IN A RANDOMIZED CLINICAL TRIAL.

DESPITE THE IMPORTANCE OF MITOCHONDRIAL FUNCTION TO MUSCLE HEALTH, IT IS UNKNOWN IF TREATMENT OF MA BENEFITS MUSCLE MITOCHONDRIAL FUNCTION, ADIPOSITY, OR ENDURANCE IN CKD. THE PROPOSED PROJECT WILL USE PRECISE, IN VIVO 31P MRS AND GOLD-STANDARD TESTING OF PERIPHERAL INSULIN SENSITIVITY BY HYPERINSULINEMIC EUGLYCEMIC CLAMP TO PROBE THE PATHOPHYSIOLOGY OF MA AND LOW ENDURANCE IN A CLINICAL TRIAL OF ALKALI THERAPY IN CKD AND MA.

WE WILL COMPARE VEVERIMER OR LOW-DOSE SODIUM BICARBONATE TO PLACEBO IN A MULTICENTER RANDOMIZED, DOUBLE-DUMMY PLACEBO-CONTROLLED, CROSS-OVER TRIAL DESIGN IN 102 PERSONS WITH MODERATE-SEVERE CKD AND MA. FIRST, WE WILL TEST THE EFFICACY OF 3-MONTHS OF ALKALI THERAPY, COMPARING VEVERIMER OR LOW DOSE SODIUM BICARBONATE VERSUS PLACEBO, ON MUSCLE METABOLIC HEALTH IN A RANDOMIZED CROSSOVER TRIAL IN MA. SECOND, TEST THE EFFICACY OF 3-MONTHS OF ALKALI THERAPY, COMPARING VEVERIMER OR LOW DOSE SODIUM BICARBONATE VERSUS PLACEBO, ON IMPROVING PHYSICAL ENDURANCE IN MA.

OUR RATIONALE IS THAT IDENTIFICATION OF THERAPEUTIC TARGETS FOR LOW PHYSICAL ENDURANCE WILL INFORM THE DEVELOPMENT OF PHARMACOLOGIC INTERVENTIONS. LONG TERM, WE EXPECT STRATEGIES TREATING MA WILL IMPROVE EXERCISE TOLERANCE, ENABLING EFFECTIVE ENGAGEMENT IN LIFESTYLE INTERVENTIONS IMPROVING QUALITY OF LIFE IN CKD.

Davis 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]

Davis, California 95616 United States

Single Zip Code

Investigator-Initiated Clinical Trials Targeting Diseases within the Mission of NIDDK (R01-Clinical Trial Required) (PA-18-330)

Amendment Since initial award the total obligations have increased 384% from $668,172 to $3,236,031.