蛋白尿是肾脏疾病的常见表现和独立危险因素。近来研究证实肾小球足细胞分子表达异常参与了蛋白尿的发生发展。Nephrin是第一个被发现的足细胞裂孔隔膜结构分子，而且其胞内酪氨酸位点磷酸化诱导的信号传导在足细胞骨架重塑中起重要作用。C-mip是新近发现的另一个重要足细胞分子，我们前期在嘌呤霉素肾病大鼠中发现肾小球c-mip表达增加而nephrin磷酸化降低，在血管紧张素II足细胞损伤模型中发现c-mip可通过cbp和Fyn途径下调nephrin的磷酸化继而引起足细胞骨架变化和细胞凋亡。本课题拟在体内、外嘌呤霉素足细胞损伤模型，采用RNAi技术特异敲低c-mip表达，进而分析c-mip介导的信号通路在足细胞损伤以及蛋白尿发生发展中的作用，以探索蛋白尿发生的新机制，也可为将来寻找新的高效而特异的蛋白尿治疗靶点提供依据。

Proteinuria is both the most common clinical manifestation in kidney disease and also the independent risk factor in progession to end stage renal failure. Many evidences demonstrated that the abnormalities of glomerular podocyte molecules are involved in the occurrence and development of proteinuria. Nephrin was identified as the first molecule of podocyte slit diaphragm, and tyrosine phosphorylation of nephrin intracellular domain plays a crucial role in the remodeling of podocyte cytoskeleton. C-maf inducing protein (c-mip) is another newly identified podocyte protein. Our priliminary results showed that 1) c-mip expression increased while nephrin phosphorylation decreased in PAN nephrotic rats, 2) angitension II-induced upregulation of c-mip expression caused remarkable podocyte apoptosis and cytoskeletal rearrangment at least partially through csk-cbp-Fyn axis in cultured mouse podocyte. The present project aims to investigate the function of c-mip-mediated signal transduction in podocyte damage and proteinuria development by applying c-mip-siRNA both in vivo and in vitrol PAN-induced podocyte injury model in order to explore the novel molecular mechanisms of proteinuria and find the potential specific and effective anti-proteinuric target.