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Role of Clathrin Mediated Endocytosis in Podocyte Biology

网格蛋白介导的内吞作用在足细胞生物学中的作用

基本信息

批准号：
9382054
负责人：
Shuta Ishibe
金额：
$ 37.69万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-27 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9382054
关键词：
Ablation Actins Applications Grants Binding Biology Biopsy Chronic Kidney Failure Clathrin DNA Sequence Alteration Data Defect Deterioration Development Dialysis procedure Disease Disease model Dynamin Dynamin 2 Dynamin I Employee Strikes End stage renal failure Endocytosis Endothelial Cells F-Actin Family Fibrosis Filtration Focal Segmental Glomerulosclerosis Foot Process Functional disorder Future GAK gene Gene Targeting Genes Genetic Genetic Transcription Histologic Human Human Genetics In Vitro Injury Investigation Kidney Kidney Failure Kidney Transplantation Knockout Mice Lead Link Maintenance Mediating Microarray Analysis Modeling Molecular Genetics Molecular Weight Mus Myosin ATPase Nephrons Nephrotic Syndrome Pathogenesis Pathway interactions Patients Permeability Physiological Plasma Play Proteins Proteinuria Public Health Regulation Renal function Renal glomerular disease Role Sampling Secondary to Serum Response Element Serum Response Factor Site Structure Testing Therapeutic Tissue-Specific Gene Expression Transgenic Mice United States coated pit genetic approach glomerular basement membrane glomerular filtration improved in vivo inhibitor/antagonist inositol-1,4,5-trisphosphate 5-phosphatase interstitial mouse model new therapeutic target novel novel therapeutics podocyte polymerization promoter repaired synaptic function synaptojanin transcription factor urinary

项目摘要

Project Summary Chronic kidney disease (CKD) often leads to irreversible deterioration of kidney function that often progresses to End Stage Kidney Disease (ESKD). CKD has emerged as a serious public health issue and data obtained from the USRDS reveals that the number 20 million patients in the United States suffer from CKD. As glomerular diseases secondary to podocyte dysfunction account for greater than 80% of all CKD, an intensive molecular and genetic approach to identify mechanisms for podocyte development, maintenance and repair may provide new therapeutic targets Recent evidence suggests an important role of clathrin mediated endocytosis orchestrating podocyte function. Using genetic mouse models, we have discovered proteins involved in mediating clathrin mediated endocytosis such as synaptojanin 1, dynamin, and endophilin, are indispensible for maintaining a normally functioning filtration barrier. We have further extended our findings that GAK, a protein important for uncoating clathrin, is equally important. To probe the mechanism, a microarray analysis on enriched glomeruli was performed revealing a plethora of actin-regulated genes containing a serum response element regulated by the serum response factor. We have also taken advantage of human kidney biopsies from patients with focal segmental glomerulosclerosis (FSGS), which also demonstrated reduced GAK expression and increased serum response factor expression. Therefore In Aim 1, we will define the fundamental mechanisms on how loss of GAK contributes to podocyte dysfunction through abnormal actin dynamics mediated by serum response factor. In Aim 2, we will characterize the role of GAK's C-terminus to stabilize podocyte function and further investigate the link between endocytosis and actin in podocytes. Our mouse models of disease with human FSGS biopsy findings provide impetus to further define the role of clathrin- mediated endocytosis in the formation and maintenance an intact glomerular filtration barrier.

项目摘要慢性肾脏疾病(CKD)通常会导致不可逆转的肾功能恶化通常进展到终末期肾病(ESKD)。CKD已经成为一个严肃的公众健康问题和从USRDS获得的数据显示，每年有2000万患者美国患上了慢性肾脏病。作为足细胞功能障碍的继发性肾小球疾病占所有CKD的80%以上，这是一种密集的分子和遗传学方法确定足细胞发育、维护和修复的机制可能会提供新的治疗靶点最近的证据表明，胞质蛋白介导的一个重要作用协调足细胞功能的内吞作用。利用遗传小鼠模型，我们发现参与介导网状蛋白介导的内吞作用的蛋白质，如突触素1，动力蛋白，和亲内素，是维持正常运行的过滤屏障所不可缺少的。我们进一步扩展了我们的发现，即GAK，一种对脱壳蛋白很重要的蛋白质，是同样重要的是。为了探讨其机制，对肾小球浓缩进行了微阵列分析。揭示了过多的包含血清反应元件的肌动蛋白调节基因受血清反应因子调节。我们还利用了人类肾脏局灶性节段性肾小球硬化(FSGS)患者的活检组织，这也是表现为GAK表达减少，血清反应因子表达增加。因此，在目标1中，我们将定义GAK丢失的基本机制通过血清反应因子介导的肌动蛋白动力学异常导致足细胞功能障碍。在目标2中，我们将表征GAK的C末端在稳定足细胞功能和进一步研究足细胞内吞作用和肌动蛋白之间的联系。我们的小鼠模型人类FSGS活检发现的疾病为进一步确定网状蛋白的作用提供了动力。介导的内吞作用在形成和维持完整的肾小球滤过屏障中的作用。