Role of CLIC5 in Podocyte Injury and Remodeling

CLIC5 在足细胞损伤和重塑中的作用

基本信息

批准号：
8770472
负责人：
Cynthia Tsui
金额：
$ 7.78万
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：
2014
资助国家：
美国
起止时间：
2014-07-28 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8770472
关键词：
Actins Adherence Adhesions Adriamycin PFS Adult Animal Model Apical Architecture Basement membrane Biochemical Biological Biological Markers Biotinylation Cell Death Cell Fractionation Cell Line Cell membrane Cell surface Cells Cessation of life Chloride Channels Chloride Ion Chlorides Chronic Kidney Failure Clinical Complex Data Disease Disease Progression Family Focal Segmental Glomerulosclerosis Foot Process Foundations Functional disorder Genetic Genetic Polymorphism Goals Hair Cells Human Immunofluorescence Microscopy In Vitro Injury Integral Membrane Protein Intervention Kidney Diseases Laboratories Length Life Literature Living Donors Maintenance Measures Mediating Mediator of activation protein Membrane Proteins Membranous Glomerulonephritis Messenger RNA Methods Modeling Molecular Morphogenesis Mus NPHS2 protein Natural regeneration Pathogenesis Patients Periodic acid Schiff stain method Prevention Process Proteins Proteinuria Public Health Recovery Renal glomerular disease Role Sampling Sialic Acids Signal Pathway Signal Transduction Staging Stereocilium Structure Testing Therapeutic Urine Variant apical membrane base cell injury cellular imaging density design experience ezrin glomerular basement membrane glomerular filtration in vivo light microscopy novel podocalyxin podocyte protein expression public health relevance repaired research study response response to injury sialylation tool trafficking

项目摘要

DESCRIPTION (provided by applicant): In many glomerular diseases, proteinuria and disease progression are associated with podocyte loss by death or detachment. Understanding the mechanisms by which the podocyte maintains attachment and recovers by remodeling its large and foot processes after injury is critical for the identification of potential therapeutic targetsof glomerular diseases. Podocalyxin is an apical membrane protein that is required for the formation of podocyte large and foot processes. A decrease in the sialylation and expression of podocalyxin are associated with glomerular diseases. Chloride intracellular channel 5 (CLIC5) is an apical membrane protein that associates with podocalyxin and ezrin, and is an important intermediate adapter between the cell membrane and the cytoskeletal network. We have recently discovered that CLIC5-deficient podocytes display foot process effacement and a decrease in podocalyxin protein expression. CLIC5 protein expression is decreased in Minimal Change Disease compared with normal human living donors. Our long term goal is to identify and understand the proteins and signaling pathways necessary for podocyte survival and remodeling in response to glomerular injury. The aims of this proposal are twofold. First, we will determine the extent to which CLIC5 controls the proper trafficking and stability of podocalyxin in podocyte processes. Second, we will identify the role of CLIC5 in maintaining podocyte adhesion in response to glomerular injury in vivo. This project is significant because we will demonstrate a novel mechanism that is critical for podocyte recovery from injury. A combination of biochemical and cell biological approaches will be employed in cultured Clic5-deficient podocytes and Clic5-deficient mice. We expect to identify CLIC5 as a protein critical for podocytes to recover by maintaining their adherence to the glomerular matrix and to remodel their foot processes to reestablish the glomerular filtration barrier. The results of these experiments may aid in establishing a foundation for the rational design of effective clinical interventions for glomerular diseases.

描述（由申请人提供）：在许多肾小球疾病中，蛋白尿和疾病进展与死亡或脱离造成的足细胞丧失有关。了解足细胞通过在受伤后重塑其大和脚部过程来保持附着的机制，这对于鉴定潜在的肾小球疾病的潜在治疗靶标至关重要。足细胞蛋白是一种顶膜蛋白，是足部和脚部过程形成所必需的。足细胞蛋白的溶苷和表达的降低与肾小球疾病有关。氯化物细胞内通道5（CLIC5）是一种顶膜蛋白，它与pocalyxin和ezrin相关，并且是细胞膜和细胞骨架网络之间的重要中间适配器。我们最近发现，Clic5缺陷型足细胞表现出脚步过程的效率和足con蛋白蛋白表达的降低。与正常的人类活体供体相比，CLIC5蛋白表达在最小变化疾病中降低。我们的长期目标是识别和理解足细胞存活所必需的蛋白质和信号通路，并响应肾小球损伤。该提议的目的是双重的。首先，我们将确定CLIC5在多capocyte过程中控制clic5的适当运输和稳定性的程度。其次，我们将确定clic5在响应体内肾小球损伤的响应中维持足细胞粘附方面的作用。该项目很重要，因为我们将展示一种新的机制，这对于从损伤中恢复的足细胞恢复至关重要。生物化学和细胞生物学方法的组合将用于培养的Clic5缺陷型足细胞和Clic5缺陷型小鼠中。我们希望将Clic5识别为足细胞通过保持肾小球基质的依从性并重塑其脚部过程以重新建立肾小球滤过屏障来恢复的蛋白质。这些实验的结果可能有助于建立有效设计肾小球疾病临床干预措施的基础。