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.
Renal glomerular diseases account for 90% of end-stage kidney disease at a cost of $20 billion per year in the US. Nephrotic syndrome is due to the defective glomerular filtration barrier. Recent studies reveal dysfunction of podocytes and renal progenitor cells play critical roles in renal glomerular pathogenesis. This notion suggests podocytes and renal progenitor cells as new therapeutical targets for the disease. Generation of new zebrafish models of nephrotic syndrome and podocyte injury, which are amenable for large-scale chemical and genetic screenings, will allow for studies of molecular mechanisms of glomerular pathogenesis and search for novel therapy for glomerular diseases.
|Hurd, Toby W; Otto, Edgar A; Mishima, Eikan et al. (2013) Mutation of the Mg2+ transporter SLC41A1 results in a nephronophthisis-like phenotype. J Am Soc Nephrol 24:967-77|
|Ashraf, Shazia; Gee, Heon Yung; Woerner, Stephanie et al. (2013) ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption. J Clin Invest 123:5179-89|
|Zhou, Weibin; Otto, Edgar A; Cluckey, Andrew et al. (2012) FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair. Nat Genet 44:910-5|
|Zhou, Weibin; Hildebrandt, Friedhelm (2012) Inducible podocyte injury and proteinuria in transgenic zebrafish. J Am Soc Nephrol 23:1039-47|
|Chaki, Moumita; Airik, Rannar; Ghosh, Amiya K et al. (2012) Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling. Cell 150:533-48|