The Role of Endocytosis and Actin Regulation in Podocytes

足细胞内吞作用和肌动蛋白调节的作用

基本信息

批准号：
8437468
负责人：
Shuta Ishibe
金额：
$ 36.12万
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 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8437468
关键词：
Actins Address Adult Age Antibodies Appearance Binding Biochemical Biology Birth Cell Culture Techniques Cell physiology Cells Chronic Kidney Failure Clathrin Cytoskeleton Data Dendritic Spines Deterioration Development Disease Dynamin Dynamin I End stage renal failure Endocytosis Filtration Focal Segmental Glomerulosclerosis Foot Process Functional disorder Funding Future Genes Genetic Goals Grant Homeostasis Human In Vitro Inflammation Injury Kidney Kidney Failure Kidney Transplantation Knock-out Knowledge Ligands Light Link Maintenance Mass Spectrum Analysis Mediating Membrane Membrane Protein Traffic Microscopic Modeling Molecular Molecular Genetics Molecular Machines Mus Mutant Strains Mice Nephrotic Syndrome Neurons Pathogenesis Pathway interactions Patients Peripheral Phenocopy Phenotype Phosphoric Monoester Hydrolases Physiological Play Presynaptic Terminals Process Protein Isoforms Proteins Proteinuria Proteomics Public Health Regulation Renal dialysis Renal function Renal glomerular disease Role Secondary to Shotguns Signal Transduction Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Synapses Therapeutic Therapeutic Agents Transgenic Mice United States Wild Type Mouse coated pit extracellular glomerular filtration in vitro Model in vivo interest mouse model novel therapeutics podocyte receptor repaired research study synaptojanin urinary

项目摘要

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) often leads to irreversible deterioration of renal 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 of new cases of ESKD in the United States is projected to exceed 700,00 patients by year 2015. As glomerular diseases secondary to podocyte dysfunction contribute up to 80% of all ESKD, a detailed molecular and genetic approach to identify mechanisms for podocyte development and repair may give us new targets for developing therapeutic agents. Recent cell culture models have described the possible role of endocytosis in podocytes. To further determine its importance, we identified important genes regulating endocytosis, synaptojanin 1, and dynamin, which when deleted in mice results in severe proteinuria and foot process effacement. We also identified endophilin, an interactor of synaptojanin 1 and dynamin through a proteomic screen, and loss of endophilin also results in severe proteinuria. Interestingly, other proteins such as CD2AP and Myo1e, which are central to the integrity of foot processes via genetic studies in humans are dynamin and synaptojanin 1 interactors. In Aim 1, we will define the fundamental mechanisms on how loss of endocytic regulation contributes to podocyte dysfunction. In Aim 2, we will characterize the role of endophilin in glomerular biology, and investigate the link between endocytosis and actin in podocytes. Lastly, in Aim 3, we will incorporate mice glomerular injury models to identify the impact of endocytosis after injury. Our results strongly implicate a protein network that controls clathrin-mediated endocytosis in the formation and maintenance of the glomerular filtration barrier. By completing these aims, we will have an opportunity to further expand our knowledge of endocytic pathways vital for podocyte homeostasis. PUBLIC HEALTH RELEVANCE: Kidney injury that results in inflammation and urinary protein loss often progress to irreparable damage where patients require a kidney transplantation or dialysis to survive. In the United States, the number of new cases of chronic kidney disease is expected to exceed 700,000 by year 2015 and the majorities are due to damage to the kidney's filtration barrier. Hence, the goal of this proposal is to unravel the fundamental mechanisms and pathogenesis of this disease process so that in the near future new therapeutic options are available.

描述（由申请人提供）：慢性肾病（CKD）通常会导致肾功能不可逆转的恶化，并常常进展为终末期肾病（ESKD）。 CKD 已成为一个严重的公共卫生问题，从 USRDS 获得的数据显示，到 2015 年，美国 ESKD 新病例数量预计将超过 70 万人。由于足细胞功能障碍继发的肾小球疾病导致80% 的 ESKD 是一种详细的分子和遗传学方法来确定足细胞发育和修复的机制，这可能为我们开发治疗药物提供新的目标。最近的细胞培养模型描述了足细胞内吞作用的可能作用。为了进一步确定其重要性，我们鉴定了调节内吞作用、突触蛋白 1 和动力的重要基因，这些基因在小鼠体内被删除时会导致严重的蛋白尿和足突消失。我们还通过蛋白质组筛选鉴定了内亲蛋白，它是突触蛋白 1 和动力蛋白的相互作用因子，内亲蛋白的缺失也会导致严重的蛋白尿。有趣的是，其他蛋白质（例如 CD2AP 和 Myo1e）是动力蛋白和突触蛋白 1 相互作用蛋白，通过人类遗传学研究，它们对足突的完整性至关重要。在目标 1 中，我们将定义内吞调节丧失如何导致足细胞功能障碍的基本机制。在目标 2 中，我们将描述内亲蛋白在肾小球生物学中的作用，并研究足细胞中内吞作用和肌动蛋白之间的联系。最后，在目标 3 中，我们将结合小鼠肾小球损伤模型来确定损伤后内吞作用的影响。我们的结果强烈暗示了在肾小球滤过屏障的形成和维持中控制网格蛋白介导的内吞作用的蛋白质网络。通过完成这些目标，我们将有机会进一步扩展我们对足细胞稳态至关重要的内吞途径的了解。公共健康相关性：导致炎症和尿蛋白丢失的肾损伤通常会发展为无法弥补的损害，患者需要肾移植或透析才能生存。在美国，到2015年，慢性肾病新发病例数预计将超过70万例，其中大部分是由于肾脏过滤屏障受损所致。因此，该提案的目标是揭示这种疾病过程的基本机制和发病机制，以便在不久的将来提供新的治疗选择。