钙调蛋白S100A16诱导细胞骨架重构参与肾脏上皮细胞间充质转分化的分子机制

肾小管间质纤维化是慢性肾脏病发展的重要病理过程，在此过程中肾小管上皮细胞间充质转分化(EMT)是发病的关键环节。细胞骨架蛋白表达与重组是EMT的重要特征。钙调蛋白S100A16是新发现的S100家族成员，其病生理功能不详。我们的前期研究表明：S100A16的过表达加重肾小管间质纤维化，促进肾小管上皮细胞EMT；质谱结果提示S100A16与大量的细胞骨架蛋白和肌动蛋白调控相关的蛋白存在相互作用(如cofilin)，对相关细胞骨架蛋白的表达和功能产生影响。我们假设各种肾脏损伤因素上调肾小管上皮中S100A16的表达，进而增强其与肌动蛋白调节蛋白的结合能力，诱发肾脏上皮细胞骨架蛋白重构和EMT的发生，参与肾小管间质纤维化的发生发展。本课题将利用临床标本、动物及分子生物学实验、蛋白质功能筛选等技术进一步证实课题假设，揭示S100A16通过诱导细胞骨架蛋白重构引起肾脏上皮细胞间充质转分化的分子机制。

Renal fibrosis, particularly tubulointerstitial fibrosis, is the common final outcome of almost all progressive chronic kidney diseases. Renal tubulointerstitial fibrosis is also a reliable predictor of prognosis and a major determinant of renal insufficiency. Epithelial-mesenchymal transition (EMT), a process by which fully differentiated epithelial cells undergo transition to a fibroblast phenotype, has emerged as an important pathway leading to generation of matrix-producing fibroblasts and myofibroblasts in renal fibrosis. A key feature of EMT is reorganization of the cytoskeleton. S100A16, a Ca+ binding protein, is a new member of S100 protein family. However, the study of S100A16 in renal tubulointerstitial fibrosis is very rare. The preliminary data from our proposed project has shown that S100A16 was a key mediator of EMT, and contributed the progression of renal tubulointerstitial fibrosis in mice model as well as human kidney disease. Moreover, we found that there were many cytoskeleton and cytoskeletal associated proteins, such as Cofilin, binding with S100A16. Based on these preliminary data, we’ll further study the molecular mechanism of S100A16 regulation of cytoskeletal reorganization during EMT in renal tubular cells and transgenic/knock out mice model. We will demonstrated how changes in gene expression patterns of cytoskeletal associated proteins during S100A16-induced EMT, and how changes in cytoskeletal architecture during EMT can regulate gene expression, thus further promoting EMT progression in renal tubulointerstitial fibrosis.