Mst1/Beclin1轴对肝星状细胞自噬的调控及其机制研究

Liver fibrosis is an excessive wound healing process caused by chronic liver disease that may progress to end-stage liver diseases. The activation and proliferation of hepatic stellate cells after liver damage leads to liver fibrosis. In recent years, autophagy was reported to play an important role in activating hepatic stellate cells and promoting them into fibroblasts. Our Previous research found that chronic liver damage can induce autophagy and apoptosis of hepatic stellate cells. Selectively inhibiting the autophagy activity of hepatic stellate cells can improve the ratio of apoptosis, thus promote the procedural death of hepatic stellate cells. On this basis, we hypothesized that there is a common pathway in hepatic stellate cells between escaping apoptosis and inducing autophagy. Beclin1 can be involved in the regulation of apoptosis and autophagy, and Mst1 can promote the combination of Beclin1 and Bcl-2/Bcl-xL to promote apoptosis and inhibit autophagy of cells. This project therefore intends to adopt carbon tetrachloride-induced hepatic stellate cells as cell models and dimethylnitrosamine-induced mice as animal models, detecting the affect of Beclin1 and Mst1 on apoptosis, autophagy and proliferation to determine the regulation effect of Mst1/Beclin1 axis on autophagy in hepatic stellate cells. This is a meaningful exploration to find effective antifibrotic drugs.

肝纤维化是慢性肝脏疾病过度创伤修复的过程，可进展为终末期肝病。肝脏损伤后肝星状细胞的活化增殖导致肝纤维化的发生。近年发现自噬在活化肝星状细胞、促进其转化为成纤维细胞中起了重要作用。本课题组前期研究发现肝脏慢性损伤能够同时诱导肝星状细胞发生自噬与凋亡现象，选择性抑制肝星状细胞的自噬活性能够提高肝星状细胞的凋亡比率，促进细胞的程序性死亡。在此基础上我们推测：慢性肝损伤时肝星状细胞逃避凋亡与诱发自噬之间存在共同通路。Beclin1能参与细胞的凋亡及自噬两条途径的调控过程，而Mst1能促进Beclin1与Bcl-2/Bcl-xL相结合，促进细胞凋亡、抑制细胞的自噬。故本项目拟以四氯化碳诱导的肝星状细胞和二甲基亚硝胺诱导的大鼠为模型，检测Beclin1及Mst1对肝星状细胞凋亡、自噬、增殖的影响，确定Mst1/Beclin1轴对肝星状细胞自噬的调控作用，为找到有效的抗肝纤维化药物作出有意义的探索。