Role of CLIC5 in Podocyte Injury and Remodeling

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离造成的损失有关。了解足细胞在损伤后通过重塑其大足突维持附着和恢复的机制对于确定肾小球疾病的潜在治疗靶点至关重要。足裂素是足细胞大突和足突形成所必需的一种顶端膜蛋白。唾液化和足alyxin表达的减少与肾小球疾病有关。细胞内氯离子通道5 （CLIC5）是一种与足alyxin和ezrin结合的顶膜蛋白，是细胞膜和细胞骨架网络之间重要的中间接头。我们最近发现，缺乏clic5的足细胞显示足突消退和足alyxin蛋白表达减少。与正常人类活体供体相比，微小变化病患者的CLIC5蛋白表达降低。我们的长期目标是识别和理解肾小球损伤时足细胞存活和重塑所必需的蛋白质和信号通路。这项建议的目的是双重的。首先，我们将确定在足细胞过程中，CLIC5在多大程度上控制足alyxin的适当运输和稳定性。其次，我们将在体内确定CLIC5在肾小球损伤反应中维持足细胞粘附的作用。该项目意义重大，因为我们将展示一种对足细胞损伤恢复至关重要的新机制。在培养的clic5缺陷足细胞和clic5缺陷小鼠中，将采用生化和细胞生物学相结合的方法。我们期望将CLIC5确定为足细胞通过维持其对肾小球基质的粘附来恢复的关键蛋白，并重塑足突以重建肾小球滤过屏障。这些实验结果可能有助于为合理设计有效的肾小球疾病临床干预措施奠定基础。

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.