Nephrin内吞在足细胞骨架改变中的作用及分子机制

Nephrin是连接足细胞足突和介导信号转导的结构分子和信号分子，在调节肌动蛋白组装及细胞骨架重排中起重要作用。Nephrin内吞与足细胞损伤密切相关，但其受哪些病理生理性信号的调节导致足细胞损伤尚不清楚。Beta-arrestinl是介导细胞膜表面受体脱敏和内吞的可溶性蛋白，可介导多种受体蛋白的内吞。我们前期研究发现高糖刺激下足细胞粘附异常、足细胞骨架发生紊乱重组。本项目拟研究高糖刺激下nephrin内吞在足细胞骨架改变中的作用和分子机制。通过建立糖尿病肾病动物模型、高糖刺激足细胞，观察高糖对nephrin内吞的影响，以及nephrin内吞对足细胞骨架的影响；通过改变beta-arrestin1表达，评价其对nephrin内吞引起足细胞骨架重排的调控作用及其调节内吞所依赖的途径。本课题将揭示nephrin内吞在疾病状态下引起足细胞损伤的机制，为寻求有效途径防止足细胞损伤提供理论依据。

Nephrin, a structural and signaling molecule, plays an important role in the regulating actin assembly and cytoskeleton reorganization. Nephrin endocytosis damages the integrity of slit diaphragm and results in podocyte injury. However, the molecular mechanisms of nephrin endocytosis in podocyte injury are still unknown. Beta-arrestinl, a soluble protein, mediates receptors endocytosis and receptors desensitization. Our studies have found that high glucose result in abnormalities of podocyte adhesion and podocyte cytoskeleton reorganization. We will focus on the role and molecular mechanisms of nephrin endocytosis in podocyte stimulated by high glucose. We will investigate the effect of high glucose on nephrin endocytosis and the effect of nephrin endocytosis on pococyte cytoskeleton. We speculate that nephrin endocytosis in this process is mediated by beta-arrestin1 in a clathrin-dependent manner or raft-dependent manner. The molecular mechanisms of nephrin endocytosis in podocyte injury will be revealed and new theoretical foundation will be found to prevent the podocyte injury.