细胞骨架异常是足细胞损伤，蛋白尿形成的关键环节。本课题组前期研究发现，Slit-ROBO RhoGTP激酶激活蛋白2（srGAP2）主要在肾小球足细胞中表达，且与多种足细胞骨架蛋白编码基因存在共表达关系。足细胞疾病中srGAP2表达下降，且与蛋白尿负相关；体外抑制srGAP2表达，可降低Cdc42、RhoA和Rac1等小分子GTP激酶表达量，后者对细胞骨架具有调控作用。因此，我们推测srGAP2在维持足细胞骨架形态和正常功能中发挥重要作用，但仍需进一步研究证实。本课题拟在前期研究基础上，利用足细胞损伤模型，通过co-IP及尾静脉质粒注射等技术，明确srGAP2对细胞骨架调节蛋白Cdc42，RhoA和RAC1的调控方式，对维持足细胞骨架结构稳定和足细胞功能的作用；及在足细胞损伤和蛋白尿形成中的意义。旨在揭示新的足细胞骨架调控和损伤的分子机制，为发现新的肾脏疾病治疗靶点提供理论依据。

The cytoskeleton injury is a main feature of podocyte lesion and chronic kidney disease (CKD). Our previous studies indicated that slit-robo Rho GTPases activating protein (srGAP2) was enriched in the podocyte, and co-expressed with several genes involved in the cytoskeleton regulation. Moreover, the expression level of srGAP2 mRNA in the glomeruli was significantly decreased and negatively associated with proteinuria in the podocytopathy. In addition, using small interfering RNA (siRNA) against srGAP2, we confirmed initially that Rho-GAP domain of srGAP2 involved in multiple signaling pathways, such as Cdc42, RhoA and Rac1. Based on above evidences, we speculate that srGAP2 may play a role to maintain the function of podocyte by the regulation of Cdc42, RhoA and Rac1. Inhibiting the expression of srGAP2 could lead to the podocyte lesion and proteinuria in kidney diseases. However, there is few study reported the effect of srGAP2 on regulation podocyte cytoskeleton. To confirm this hypothesis, we will employ in vivo and vitro experiments to investigate the effects of srGAP2 on the podocyte injury and proteinuria initiation, and its potential mechanisms. The results of this study is expected to demonstrate the potential molecular mechanisms of srGAP2 associated with the cytoskeleton regulation of podocyte, and reveal the new target for the treatment of podocyte lesion and proteinuria in renal diseases.