Hippo通路在急性肾损伤发病中的作用及其机制

项目名称： Hippo通路在急性肾损伤发病中的作用及其机制

项目编号： No.81200499

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学二处

项目作者： 许晶

作者单位： 中国人民解放军第二军医大学

项目金额： 23万元

中文摘要： 急性肾损伤（AKI）后减少小管细胞凋亡、促进其再生对AKI的治疗具有重要意义。近年研究发现发育相关的Hippo通路在器官组织损伤后修复中具重要作用。前期研究在I/R AKI大鼠发现损伤期肾组织Mst1表达显著升高，修复期却显著降低，与肾功能和组织损伤程度变化一致。因而我们推测Hippo通路在I/R AKI损伤期和修复期可能具有不同的调控作用。拟进一步通过大鼠AKI模型和肾脏特异性条件性基因敲除小鼠Mst1 Cre/Loxp观察AKI各期Mst1以及下游YAP和关键增殖凋亡相关基因、细胞周期蛋白差异表达；体外调控Mst1在正常和I/R大鼠NRK-52E细胞内表达，研究其在肾损伤修复中的作用，并对其下游信号通路进行系统研究。构建腺病毒载体，经肾静脉注射导入动物模型体内，观察损伤期下调和修复期上调Mst1对肾损伤和修复的影响，探讨Mst1调控AKI分子机制，为治疗提供新的靶点和手段。

中文关键词： 急性肾损伤；肾纤维化；修复；Hippo 信号通路；YAP

英文摘要： When normal kidney tubular epithelial cells encountered ischemia/reperfusion (I/R) injury, there was a marked increase in cell death by necrosis and apoptosis. Different from the heart or brain, the kidney could achieve completely recovery by the proliferation and differentiation of the surviving cells if the insult was mild or did not last very long; tipical cases could experience several stages after acute kidney injury (AKI), including injury (<48h), repair (48h-5d) and late repair (5d-7d) stage. however, the repair could be maladaptive if the injury was too severe. This could result in varying degrees of chornic kidney diseases; some might eventually progress to end stage renal disease and rely on dialysis or transplantation. Hippo pathway, with mammlian Ste-20 like kinase 1(Mst1)as one of its most critical core kinases, has recently been found to be an significant signaling pathway that balance the proliferation and apoptosis of cells in organism.Our prelimilary studies in rat kidney I/R model showed that renal Mst1 level increased significantly in the injury stage but desreased significantly in the repair stage, which was identical to the change of renal function and the extent of the damage of the renal tissue. Thus, we assumed that hippo pathway could play different role in the injury and repair stages o

英文关键词： acute kidney injury；renal fibrosis；repair；Hippo pathway；yes-associated protein