Wipi2介导的Cx50-Atg16L1复合体调控人晶状体上皮细胞自噬前体膜结构形成及其药物分子干预靶点研究

白内障是全球首要致盲眼病。探究白内障疾病相关候选基因分子作用通路寻找相应药物干预靶点是白内障临床防治新思路。本课题组前期研究首次证实，白内障疾病相关候选基因缝隙连接蛋白50（简称Cx50）基因敲除斑马鱼动物模型的白内障表型与自噬异常有关，并在晶状体上皮细胞中通过形成Cx50-Atg16L1复合体参与自噬调控，并与自噬前体膜形成过程的上游Wipi2蛋白相关。本项目拟在动物模型和细胞分子水平，从自噬膜形成启动到成熟过程中Cx50-Atg16L1相关上下游分子通路改变入手，探究Wipi2蛋白介导的Cx50-Atg16L1复合体调控人晶状体上皮细胞自噬前体膜结构形成过程中的分子网络体系及关键步骤，并通过Wipi2上游mTOR通路抑制剂雷帕霉素及其小分子替代物拯救实验探究其中的药物分子干预靶点及拯救方案，以期从晶状体自噬角度探索白内障的发病机制，寻找白内障新的药物防治靶点，为临床工作提供新思路。

Cataracts are the leading cause of blindness worldwide. A new mean to confront the latest clinical treatment for cataract is to explore the possible drug targets from the pathological mechanisms causing by cataract-related genes. In our previous studies, we identified it firstly that one of cataract-related genes, Cx50，knock out zebrafish develops cataract, partly resulting from the deficiency of autophagy, and Cx50 protein modulates autophagy in human lens epithelial cells（HLE cells）by forming Cx50-Atg16L1 complex and being related with Wipi2, which is the upstream protein of autophagosome biogenesis and locating in phagophore. Therefore, in order to elucidate the underlying mechanisms that Cx50-Atg16L1 complex modulates the processes in autophagosome biogenesis,such as the formation of phagophore, mediated by Wipi2 and figure out the candidate medical targets for cataract, we suppose to discover the molecular mechanisms in the role that Cx50-Atg16L1 complex plays in the formation and maturation of autophagosome in HLE cells and the rescue targets in the upstream cellular pathways for cataract, such as rapamycin and similar molecular substitutes, via cell lines and animals experiments.