Girdin蛋白下调经Akt-GSK3β途径损伤线粒体致足细胞凋亡

项目名称： Girdin蛋白下调经Akt-GSK3β途径损伤线粒体致足细胞凋亡

项目编号： No.81500541

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 任雅丽

作者单位： 北京大学

项目金额： 17万元

中文摘要： 足细胞损伤是慢性肾脏病的共同特征及病程进展的中心始动因素，细胞凋亡是其重要途径,线粒体损伤则是导致足细胞凋亡的主要因素之一，但目前对线粒体损伤的分子机制所知有限。已知足细胞中过表达细胞骨架相关蛋白Girdin会引起Akt活性升高，保护细胞免于凋亡，Girdin下降则效应相反；对肝癌细胞系的研究发现，过表达Girdin在活化Akt的基础上致其下游GSK3β活性下降。由于申请人前期发现阿霉素大鼠足细胞Girdin表达下降，同时在肿瘤细胞中发现Girdin下降可致线粒体损伤，因此我们认为Girdin下降通过Akt/GSK3β途径引起线粒体损伤致足细胞凋亡。本研究将通过培养的足细胞和动物模型分析Girdin表达情况、足细胞线粒体形态和功能变化及足细胞凋亡间的关系，进而改变足细胞Girdin水平来验证其通过Akt/GSK3β途径损伤线粒体的机制。本研究结果能为深入了解足细胞损伤的分子机制提供证据。

中文关键词： 足细胞；凋亡；线粒体；Girdin

英文摘要： Podocyte injury is a common feature of chronic kidney disease and is a central initiating factor contributed to the progression of this kind of diseases. Apoptosis is one major approach of podocyte injury. It is known that mitochondrion damage can lead to cell apoptosis. Until now, very little was known about the molecular mechanisms that were believed to be involved in mitochondrion damage. It was reported that over-expression of cytoskeleton-associated protein Girdin can lead to elevated activity of Akt and then protect podocyte against apoptosis, whereas low-expression of Girdin lead to increased apoptosis. It was also known in liver cancer cells that high level of Girdin could activate Akt followed by a decreased activity of GSK3β, which is the downstream molecular of Akt. In our previous research, we found that Girdin in podocyte was decreased in adriamycin-induced podocyte injury model. We also found that the number of deformed mitochondria increased when Girdin was knocked out in some tumor cell lines. The above clues suggested that downregulation of Girdin can lead to podocyte apoptosis by damaging mitochondria through the way of Akt/GSK3β. In this study, we will explore the corresponding molecular mechanism by analyzing the expression of Girdin, the variation of the shape and function of mitochondria, and the ratio of apoptotic podocyte and further by altering the level of Girdin in podocyte. The results of this study will provide a new understanding for the pathogenesis of podocyte injury.

英文关键词： podocyte;apoptosis;mitochondrion;Girdin