Regulation of Podocyte Actin Cytoskeleton

足细胞肌动蛋白细胞骨架的调节

• 批准号: 8290587
• 负责人: PUNEET GARG
• 金额: $ 15.5万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8290587
• 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

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）： 终末期肾病（ESRD）是一个重要的公共卫生问题。根据 2005 年 USRDS 数据，ESRD 患者使用了 19.2% 的医疗保险支出（213 亿美元）。糖尿病肾病和肾小球肾炎约占透析患者的 56.5%。肾小球是肾脏的过滤单位。足细胞是形态独特的细胞，具有章鱼样突起（足突），相互交叉形成裂隙隔膜。大多数肾小球疾病表现为蛋白尿和足细胞足突消失。我们的实验室已经确定了缝隙隔膜蛋白用于调节足细胞肌动蛋白细胞骨架的信号机制。这些信号传导机制似乎对于维持该细胞的独特结构和功能至关重要。其中几种基因产物（如 Nephrin、Podocin 和 α actinin-4）的人类突变会导致足突消失和蛋白尿，并导致肾脏疤痕，导致肾功能衰竭，最终导致需要透析的终末期肾病。该应用的指导假设是裂隙隔膜蛋白复合物调节足细胞肌动蛋白细胞骨架动力学。根据我们的前期工作，该项目将重点关注该机制的几个方面。具体来说，我们将： (1) 研究 Nephrin 和 Neph1 在肌动蛋白聚合中合作的信号机制。我们的初步数据表明 nWASP 和 cortactin 在 Nephrin/Neph1 介导的肌动蛋白聚合中发挥作用。已知这些蛋白质可以组装、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 Nephrin 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 Nephrin 和 cofilin 之间的信号传导关系。 Cofilin 是肌动蛋白聚合和重塑所必需的。 3. 为了进一步表征肌丝蛋白丝切蛋白在足细胞发育和足细胞损伤中的生理作用，我们将以足细胞特异性方式设计和表达删除肌丝蛋白丝切蛋白的小鼠。