Regulation of Podocyte Actin Cytoskeleton

足细胞肌动蛋白细胞骨架的调节

基本信息

批准号：
7994909
负责人：
PUNEET GARG
金额：
$ 5.4万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-16 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7994909
关键词：
Actins Address Adult Affect Biochemical Biological Biology Blood capillaries Cell Culture Techniques Cell physiology Cells Child Cicatrix Complex Congenital Nephrotic Syndrome Cytoskeleton Data Development Diabetic Nephropathy Dialysis procedure Disease End stage renal failure Endothelium Engineering Event Foot Process Gap Junctions Genes Glomerular capsule structure Glomerulonephritis HIV Human Injury Intercellular Junctions Kidney Kidney Diseases Kidney Failure Kidney Glomerulus Lead Mediating Medicare Microfilaments Modeling Molecular Morbidity - disease rate Morphology Mus Mutate Mutation NPHS2 protein Nephrotic Syndrome Octopus Outcome Patients Physiological Play Process Proteins Proteinuria Public Health Publishing Regulation Renal glomerular disease Research Personnel Role Secondary to Signal Transduction Structure Techniques Vasculitis Wiskott-Aldrich Syndrome Work alpha Actinin base capillary cofilin glomerular basement membrane glomerulosclerosis human EMS1 protein insight mortality mouse model nephrin podocyte polymerization positional cloning programs protein complex relating to nervous system research study response to injury slit diaphragm synergism

项目摘要

DESCRIPTION (provided by applicant): End stage renal disease (ESRD) is an important public health issue. Based on 2005 USRDS data ESRD patients utilize 19.2 percent of medicare spending (21.3 billion dollars). Diabetic nephropathy and glomerulonephritis contributes about 56.5 percent of the incident patients on dialysis. Glomerulus is the filtering unit of the kidney. Podocytes are morphologically unique cells, which have octopus-like processes (foot processes) which interdigitate to form the slit diaphragm. Most glomerular diseases present with proteinuria and podocyte foot process effacement. Our lab has identified signaling mechanisms employed by slit diaphragm proteins to regulate the actin cytoskeleton of the podocyte. These signaling mechanisms appear to be essential for maintaining the unique structure and function of this cell. Human mutations of several of these gene products such as Nephrin, Podocin, and alpha actinin-4 lead to foot process effacement and proteinuria and result in scarring of the kidney causing renal failure and eventually end stage renal disease requiring dialysis. The guiding hypothesis of this application is that the slit diaphragm protein complex regulates podocyte actin cytoskeletal dynamics. Based on our preliminary work, this project will focus on several aspects of this mechanism. Specifically we will: (1) Investigate signaling mechanisms by which Nephrin and Neph1 cooperate in actin polymerization. Our preliminary data suggests a role for nWASP and cortactin in Nephrin/Neph1 mediated actin polymerization. These proteins are known to assemble, promote, regulate and stabilize the actin polymerization complex. Using biochemical and cell biological techniques we will characterize the interaction of these two proteins with Nephrin and Neph1. (2) Investigate the role of cofilin in podocyte actin cytoskeletal dynamics. Our preliminary data shows a signaling relationship between Nephrin and cofilin. Cofilin is necessary for actin polymerization and remodeling. 3. To further characterize the physiological role of cofilin in podocytes in development and in podocyte injury, we will engineer and phenotye mice deleted of cofilin in a podocyte-specific fashion.

描述（由申请人提供）：末期肾脏疾病（ESRD）是一个重要的公共卫生问题。基于2005年USRDS数据，ESRD患者利用19.2％的医疗保险支出（213亿美元）。糖尿病性肾病和肾小球肾炎在透析中占56.5％的患者。肾小球是肾脏的过滤单元。足细胞是形态上独特的细胞，它们具有章鱼样过程（脚步过程），可与形成缝隙膜片形成。大多数肾小球疾病存在蛋白尿和足细胞脚步进料。我们的实验室已经确定了缝隙diaphragm蛋白采用的信号传导机制来调节足细胞的肌动蛋白细胞骨架。这些信号传导机制似乎对于维持该单元的独特结构和功能至关重要。其中几种基因产物的人类突变，例如肾素，Podocin和Alpha actinin-4导致脚步过程和蛋白尿，并导致肾脏疤痕，导致肾衰竭，并最终导致需要透析的肾脏肾脏疾病。该应用的指导假设是缝隙膜片蛋白复合物调节足细胞肌动蛋白细胞骨架动力学。根据我们的初步工作，该项目将重点放在该机制的几个方面。具体而言，我们将：（1）研究肾素和NEPH1在肌动蛋白聚合中合作的信号传导机制。我们的初步数据表明NWASP和Cortactin在肾蛋白/NEPH1介导的肌动蛋白聚合中的作用。已知这些蛋白质会组装，促进，调节和稳定肌动蛋白聚合复合物。使用生化和细胞生物学技术，我们将表征这两种蛋白质与肾蛋白和NEPH1的相互作用。（2）研究Cofilin在足细胞肌动蛋白细胞骨架动力学中的作用。我们的初步数据显示了肾素和Cofilin之间的信号传导关系。 Cofilin对于肌动蛋白聚合和重塑是必需的。 3。为了进一步表征Cofilin在发育和足细胞损伤中的生理作用，我们将以Podocyte特异性的方式来设计由Cofilin删除的cofilin。