Mesonephric Model of Podocyte Injury and Regeneration

足细胞损伤与再生的中肾模型

• 批准号: 8092034
• 负责人: Weibin Zhou
• 金额: $ 9万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8092034
• 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; Screening procedure; 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; stem; urinary; working group; zebrafish development

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：这个K99/R00申请的目的是利用我开发的一种新的动物模型系统来研究肾病综合征和足细胞再生的分子机制。这将有助于我的研究生涯过渡到一个独立的调查员的位置。肾病综合征（NS）是一种以蛋白尿、低白蛋白血症、水肿和高脂血症为特征的肾脏疾病，由于肾小球滤过屏障（GFB）功能的破坏。超过75%的类固醇抵抗性肾病综合征（SRNS）病例的病因尚不清楚，没有有效的治疗方法可用于该疾病，可导致局灶节段性肾小球硬化（FSGS）并导致终末期肾病（ESKD）。最近对SRNS遗传原因的发现和足细胞损伤啮齿动物模型的研究揭示了足细胞在GFB正常功能和NS发病机制中的关键作用。然而，NS的啮齿动物模型不适合用于该疾病治疗药物的高通量筛选。最近的研究发现，成人肾脏中的一个肾祖细胞亚群能够再生肾上皮细胞，包括足细胞，这为肾病综合征的治疗提供了一种新的基于干细胞/祖细胞的方法。然而，足细胞的再生机制尚不清楚。为了解决这些问题，我建议建立斑马鱼中肾作为肾病综合征的新模型系统：(1)利用我所产生的转基因斑马鱼模型来筛选改善蛋白尿的化学物质；(2)研究表达wt1b的肾祖细胞在斑马鱼足细胞再生中的潜能及足细胞再生过程中的基因表达；(3)利用已建立的GFB试验筛选温度敏感型肾病斑马鱼突变体，并确定NS的新遗传原因。完成拟议的研究将提供(1)新的化合物，可用于NS的治疗；(2)足细胞再生机制的新认识；(3)涉及NS发病机制的新基因；(4)新的斑马鱼模型。作为密歇根大学儿科与传染病系博士后，我致力于将斑马鱼中肾细胞发展成为一种新的肾病综合征动物模型系统作为我的近期职业目标。我的长期职业目标是成为肾脏研究领域的独立研究者，专注于肾脏疾病的动物模型。该奖项的培训（K99）阶段将由霍华德休斯医学研究所的研究员、儿科肾脏疾病（包括肾病综合征）人类遗传学领域国际公认的领导者Friedhelm Hildebrandt博士指导。密歇根大学在肾脏发育、肾脏疾病、斑马鱼发育和遗传学方面有几十个活跃的合作研究小组，这为我的培训和职业发展提供了理想的环境。