Role of CLIC5 in Podocyte Injury and Remodeling

CLIC5 在足细胞损伤和重塑中的作用

• 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
• 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

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足细胞死亡或脱落造成的足细胞损失相关。了解足细胞在损伤后通过重塑其大突和足突来维持附着和恢复的机制对于识别肾小球疾病的潜在治疗靶点至关重要。足糖萼蛋白是足细胞大突和足突形成所需的顶端膜蛋白。足糖萼蛋白的唾液酸化和表达减少与肾小球疾病相关。氯离子胞内通道5（CLIC 5）是与足糖萼蛋白和埃兹蛋白缔合的顶端膜蛋白，并且是细胞膜和细胞骨架网络之间的重要中间衔接子。我们最近发现，CLIC 5缺陷足细胞显示足突消失和podocalyxin蛋白表达减少。与正常人活体供体相比，微小病变疾病中CLIC 5蛋白表达降低。我们的长期目标是识别和理解肾小球损伤后足细胞存活和重塑所必需的蛋白质和信号通路。这项建议有两个目的。首先，我们将确定CLIC 5控制足细胞过程中足糖萼蛋白的适当运输和稳定性的程度。其次，我们将确定CLIC 5在维持足细胞粘附中的作用，以响应体内肾小球损伤。该项目意义重大，因为我们将展示一种对于足细胞从损伤中恢复至关重要的新机制。将在培养的Clic 5缺陷足细胞和Clic 5缺陷小鼠中采用生物化学和细胞生物学方法的组合。我们期望将CLIC 5鉴定为足细胞通过维持其对肾小球基质的粘附而恢复的关键蛋白，并重塑其足突以重建肾小球滤过屏障。这些实验的结果可能有助于建立一个基础，合理设计有效的临床干预肾小球疾病。