K08DK143339

Regulation of GLIS3, a ciliary transcription factor that prevents kidney cysts - Abstract/Project Summary

This application presents a five-year mentored research and training plan that will prepare Dr. Gabriel Loeb to lead a successful independent academic research program focused on the mechanisms underlying ciliary kidney diseases.

Dr. Loeb completed his MD and PhD at the Tri-Institutional MD-PhD Program at Weill Cornell Medical College/Rockefeller University/Memorial Sloan Kettering where he studied the function of microRNAs in the lab of Dr. Alexander Rudensky.

Dr. Loeb completed his fellowship in nephrology at UCSF and his long-term career goal is to advance our understanding of the mechanisms underlying genetic forms of kidney disease, particularly those caused by mutations in proteins that localize to primary cilia including autosomal dominant polycystic kidney disease and nephronophthisis.

This project will lay the foundation for his independent research program, by dissecting ciliary pathways involved in kidney cystogenesis.

Mutation in either of two ciliary membrane proteins, PKD1 and PKD2, is responsible for most autosomal dominant polycystic kidney disease.

However, the effectors of PKD1/PKD2 signaling remain unknown.

GLIS3 is a transcription factor that localizes to primary cilia and the cell nucleus.

Loss of GLIS3 phenocopies the severe cystogenesis caused by loss of PKD1 or PKD2.

These data suggest the hypothesis that GLIS3 is a long-sought effector of ciliary PKD1/PKD2 signaling.

This hypothesis is tested in two independent aims by 1) testing whether GLIS3 is regulated by polycystins and acts downstream of polycystins to prevent cystogenesis and 2) testing whether GLIS3 traffics from primary cilia to the nucleus and is regulated by ciliary signaling mediators.

This work will employ innovative approaches to study ciliary signaling to generate fundamental knowledge about the pathways underlying cystic kidney disease.

The proposed career development plan includes training to help establish Dr. Loeb’s ability to dissect pathways involved in genetic forms of kidney disease using mouse models, organoid models, and advanced imaging.

In addition, the training plan will help Dr. Loeb develop all the non-experimental skills necessary for a career as a successful independent academic investigator.

These additional skills include laboratory leadership, trainee mentoring and supervision, and grant writing.

Dr. Loeb has assembled a world-class mentorship team with complementary expertise in mouse models and ciliary signaling (primary mentor, Dr. Jeremy Reiter), imaging and ciliary ion channels (co-mentor Dr. Markus Delling), organoids and kidney disease models (advisory committee member Dr. Andrew McMahon), ciliary biochemistry and protein analysis (advisory committee member Dr. Maxence Nachury), polycystic kidney disease (advisory committee member Dr. Meyeon Park), and human genetics and single-cell genomics (Dr. David Erle).

Dr. Loeb, his mentors, and the Department of Medicine at UCSF are fully committed to this proposal and to his goal of becoming an independent scientist-nephrologist by the completion of this training period.

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

Mentored Clinical Scientist Research Career Development Award (Parent K08 Independent Clinical Trial Not Allowed) (PA-24-182)

Amendment Since initial award the total obligations have increased 99% from $176,244 to $350,988.