Mesonephric Model of Podocyte Injury and Regeneration

足细胞损伤与再生的中肾模型

• 批准号: 8630209
• 负责人: Weibin Zhou
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8630209
• 关键词: Accounting; Address; Adult; Animal Model; Award; Biological Assay; Biological Models; Biology; Cells; Chemicals; Childhood; Commit; Communicable Diseases; Cyclosporine; Diploidy; Disease; Disease model; Edema; End stage renal failure; Environment; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Extravasation; Focal Segmental Glomerulosclerosis; Focal glomerulosclerosis; Functional disorder; Gene Expression; Generations; Genes; Genetic; Genetic Screening; Glomerular capsule structure; Goals; Hematopoietic stem cells; Human; Human Genetics; Hyperlipidemia; Hypoalbuminemia; Infusion procedures; Injury; Institutes; Kidney; Kidney Diseases; Lead; Mammals; Medical; Mentors; Mesonephric structure; Michigan; Modeling; Molecular; Mus; Mutagenesis; Mutation; NPHS2 protein; Natural regeneration; Nephroblastoma; Nephrosis; Nephrotic Syndrome; Pathogenesis; Phase; Play; Positioning Attribute; Proteins; Proteinuria; Renal glomerular disease; Research; Research Personnel; Rodent Model; Role; Stem cells; Steroid Resistance; System; Temperature; Testing; Therapeutic; Training; Transgenes; Transgenic Model; Transgenic Organisms; Universities; Whole Organism; Zebrafish; base; career; career development; chemical genetics; cost; effective therapy; glomerular filtration; glomerulosclerosis; high throughput screening; insight; mutant; nephrin; nephrogenesis; neurotensin mimic 2; novel; pediatric department; podocyte; positional cloning; regenerative; renal epithelium; repaired; screening; stem; urinary; working group; zebrafish development

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.

摘要