蛋白尿是肾小球疾病进展及出现并发症的独立且重要危险因素之一，研究表明足细胞在蛋白尿形成中发挥着重要作用。我们前期研究发现蛋白磷酸酶2A足细胞特异性敲除小鼠（PP2A-KO）在5周龄出现蛋白尿，足细胞Synaptopodin表达下调及细胞骨架改变，PP2A-KO小鼠原代足细胞YB1的S163及S174磷酸化出现上调，而YB1蛋白表达下调。既往研究表明YB1细胞核内外分布与YB1的磷酸化有关。因此我们推测YB1蛋白的S163及S174磷酸化可引起YB1 细胞核内外分布变化及YB1的下调，进而调节Synaptopodin的表达及细胞骨架，引起足细胞损伤，引发蛋白尿。本课题拟从体外和体内实验等多层次明确YB1对Synaptopodin及细胞骨架的影响，YB1蛋白的S163及S174位点磷酸化参与足细胞损伤及蛋白尿形成中的分子机制。为降低足细胞损 伤，减轻蛋白尿，延缓肾脏疾病找到治疗靶点。

Proteinuria is not only a well-recognized sign of kidney disease but also an independent risk factor for the progression of renal failure. Podocytes are well-differentiated cells that together with the glomerular basement membrane and the adjacent fenestrated endothelial cell form the glomerular filtration barrier. Podocyte have been identified to play a key role in keeping the functional integrity of glomerular filtration and preventing plasma protein leakage to urine. Mice specific deletion of PP2A in podocytes was sufficient to cause proteinuria at 5 weeks of age, podocyte foot process effacement. Loss of PP2A in the podocyte resulted in the cytoskeleton rearrangement and down-regulation of synaptopodin. Then the Label-Free Comparative Proteomics Analysis suggest the molecular mechanism of PP2A in the podocyte maybe that the PP2A regulate the phosphorylation the site S163 and S174 of YB1. It was identified that YB1 was accumalated to the Nucleus when phosphoryled at Ser102. So we speculated that the phosphorylation of S163 and S174 of YB1 regulate the cytoskeleton rearrangement and the expression of synaptopodin, thus to cause the podocyte damage. This project intend to clarify the mechanism both at the cellular level and in vivo experiment and find the new target and the technical program of intervention or reverse of podocyte damage.