Mesonephric Model of Podocyte Injury and Regeneration
Principal Investigator: Weibin Zhou
Abstract: ABSTRACT The objective of this K99/R00 application is to utilize a new animal model system that I have developed for the study of molecular mechanisms of nephrotic syndrome and podocyte regeneration. This will aid the transition of my research career toward an independent investigator position. Nephrotic syndrome (NS) is a kidney disease characterized by proteinuria, hypoalbuminemia, edema, and hyperlipidemia, due to the disruption of renal glomerular filtration barrier (GFB) function. The causes of over 75% of steroid resistant nephrotic syndrome (SRNS) cases are still unknown and no effective therapy is available for the disease, which results in focal segmental glomerular sclerosis (FSGS) and leads to end-stage kidney disease (ESKD). Recent discoveries of genetic causes of SRNS and studies of rodent models of podocyte damage revealed the pivotal role of podocytes in the normal function of GFB and the pathogenesis of NS. However, rodent models for NS are not suitable for high-throughput screening of therapeutical agents for the disease. Recent studies have identified a subset of renal progenitor cells in adult human kidney that are capable of regenerating renal epithelial cells, including podocytes, suggesting a novel stem/progenitor cell-based approach for the treatment of nephrotic syndrome. However, little is known about the regenerative mechanism of podocytes. To address these questions, I propose to establish zebrafish mesonephros as a new model system for nephrotic syndrome by: (1) utilizing the transgenic zebrafish models that I have generated to screen for chemicals ameliorating proteinuria;(2) investigating the potential of wt1b-expressing renal progenitor cell to regenerate podocytes in zebrafish and gene expression during podocyte regeneration;(3) using the established GFB assay(s) to screen for temperature-sensitive nephrotic zebrafish mutants and identify novel genetic causes of NS. Accomplishment of the proposed research will provide (1) new chemical compounds that can lead to therapies for NS;(2) new insights into the mechanism of podocyte regeneration;(3) new genes that are involved in the pathogenesis of NS;and (4) new zebrafish models for the disease. Being a postdoctoral research fellow in the Department of Pediatrics and Communicable Diseases, University of Michigan, I am committed to develop zebrafish mesonephros into a new animal model system for nephrotic syndrome as my immediate career goal. My long-term career goal is to establish myself as an independent investigator in the field of kidney research, focusing on animal models of kidney diseases. The training (K99) phase of this award will be mentored by Dr. Friedhelm Hildebrandt, who is an investigator of Howard Hughes Medical Institute and internationally recognized leader in the fields of human genetics of pediatric kidney diseases, including nephrotic syndrome. University of Michigan has dozens of active and collaborative research groups working on kidney development, kidney diseases, and zebrafish development and genetics, which provides an ideal environment for my training and career development.
Funding Period: 2013-06-01 - 2016-05-31
more information: NIH RePORT
- Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathiesHeon Yung Gee
Division of Nephrology, Department of Medicine, Boston Children s Hospital, Harvard Medical School, Boston, Massachusetts, USA
Kidney Int 85:880-7. 2014..This approach can be extended to other rare recessive disorders, thereby providing accurate diagnosis and facilitating the study of disease mechanisms. ..
- The Shelf Live Evaluation of Investigational Dosage FormsJonathan White; Fiscal Year: 2013..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
- Mechanisms of proteinuria induced by RhoA GTPasesRobert Spurney; Fiscal Year: 2013..If the studies are successful, this signaling pathway would be an important therapeutic target for the development of drugs to prevent kidney failure. ..
- T CELL MEMORY TO PATHOGENS: GENERATION AND FUNCTIONSusan L Swain; Fiscal Year: 2013..abstract_text> ..
- A role for mRNA transport and local translation in podocytesValérie A Schumacher; Fiscal Year: 2013..A greater understanding of this physiologic pathway may eventually result in the design of new therapeutic agents that will prevent irreversible damage to podocyte foot processes and ESRD. ..
- Podocyte Hypertrophy and StressROGER CHARLES WIGGINS; Fiscal Year: 2013..The focus of this application is therefore both timely and important as we strive to reduce the prevalence of ESKD currently costing >$50 billion annually with high mortality and morbidity for patients and their families. ..
- GDNF and Ret are critical for glomerular development, maintenance, and protectionCYNTHIA TSUI; Fiscal Year: 2013..The goal of our proposal Is to understand these mechanisms and to discover molecules controlling the growth and health of the podocyte with the intent that this knowledge will facilitate the development of new therapeutic strategies...
- George M. O'Brien Kidney Center at YalePeter S Aronson; Fiscal Year: 2013..abstract_text> ..
- Caloric Restricted Rodent ColonyRICK MORIN; Fiscal Year: 2013..The purpose of this project is to develop, maintain and distribute a standing colony ofaged, calorically restricted rodents ofdefined strains for use by investigators in studies of aging. ..
- Genomics for Transplantation: Discovery and BiomarkersDaniel R Salomon; Fiscal Year: 2013..Ultimately, we hope to create the genomic tools that will allow physicians to optimize and personalize the safety and efficacy of immunosuppression. ..
- Discover and functionally characterize full-penetrance causes of nephrosis/FSGSFriedhelm Hildebrandt; Fiscal Year: 2013..SA 3. For newly identified SRNS/SSNS genes study the gene function and therapeutic approaches in zebrafish and mouse models, including Coq6-/-. ..
- Cytokine based murine focal glomerulosclerosis model a prelude to novel therapyVirginia J Savin; Fiscal Year: 2013..The approach, which combines studies of empiric therapies and of basic cellular signaling responses, will permit the design of effective therapy for future use in humans. ..
- Role of Par1 Polarity Proteins in Podocyte Development and Glomerular DiseaseKIMBERLY JEAN REIDY; Fiscal Year: 2013....
- Comparative Biology of Tissue Repair, Regeneration and AgingKevin Strange; Fiscal Year: 2013..The proposed COBRE will greatly enhance MDIBL's growth and development, which in turn will contribute to the continued growth and enhancement of the biomedical research infrastructure in Maine. ..
- Expanding Excellence in Developmental Biology in OklahomaLinda F Thompson; Fiscal Year: 2013..abstract_text> ..
- Cadiorenal and Metabolic Diseases Research CenterJohn E Hall; Fiscal Year: 2013..abstract_text> ..
- HORMONAL REGULATION OF BLOOD PRESSUREMichal Laniado Schwartzman; Fiscal Year: 2013..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
- Regulatory Mechanisms In Intestinal MotilityKenton M Sanders; Fiscal Year: 2013..The investigative team is highly synergistic and collaborative, and the PPG has a long track-record of productivity and novel discovery ..
- Genetics of Renal End Organ Damage in HypertensionMichael R Garrett; Fiscal Year: 2013..abstract_text> ..
- HIGH-THROUGHPUT IN VIVO SUBCELLULAR-RESOLUTION VERTEBRATE SCREENING PLATFORMMehmet Fatih Yanik; Fiscal Year: 2013..To demonstrate system capabilities, we will perform the first large-scale in vivo chemical screen for regenerating micro-surgically injured spinal-cord fibers. ..
- Regulation of podocyte survival by dendrinKirk N Campbell; Fiscal Year: 2013..Injury to these cells is an important mechanism in the progression of proteinuric kidney diseases. ..
- Neural Mechanisms of ItchROBERT H LA MOTTE; Fiscal Year: 2013..abstract_text> ..
- Sidekick-1 Upregulation in Podocytes Induces FSGS by Disrupting MAGI-1 FunctionLewis Kaufman; Fiscal Year: 2013..In this project, we identify a novel mechanism that contributes greatly to the pathogenesis of this important disease and may lead to the identification of novel potential therapeutic targets. ..
- A New Locus for Hereditary FSGS on Chromosome 2pRASHEED ADEBAYO GBADEGESIN; Fiscal Year: 2013....