猪源HEV感染对长爪沙鼠肝细胞线粒体自噬/凋亡平衡的影响及其分子机制研究

Hepatitis E（HE） is a prevalent zoonosis world wide. In recent years，the number of people who was infected by hepatitis E virus (HEV) and died due to hepatitis E was increased. The health department and public had paid attention to this issue. It is necessary to do research on the pathogenesis of HEV, and find the effective way to prevent and treat HEV infection. In our previous study, we demonstrated that HEV infection caused the liver injury. And one of the reason for the injury is the disorder of the structure and function of mitochondrion in hepatocyte. According to the reference, the structure and function of mitochondrion may regulate the life cycle of cells. However, the mechanism of the liver injury due to the disorder of the structure and function of mitochondrion in hepatocyte during HEV infection was not clearly yet. On the basis of the previous study, this project will combine the morphology and the function of mitochondrion with the localization and quantity，to demonstrate the pathogenesis of HEV. The mitochondrion mediated apoptosis pathway and the PINK/Parkin pathway of mitophagy as the breakthrough point, we aim to find the key factor which adjust the balance of mitophagy/apoptosis in hepatocyte during HEV infection and reveal the effctive of HEV infection to the balance of mitophagy/apoptosis in hepatocyte and its molecular mechanism. In addition, the project can support the theoretical data to the choice of target drug therapy in clinical, and provide formulate feasible strategy to prevention HEV infection.

戊型肝炎（HE）是一种世界范围内流行的人畜共患病。近几年我国HE患病人数和死亡人数呈上升趋势，引起卫生部门与公众的重视。深入研究戊型肝炎病毒（HEV）的致病机制，进而有效防治HE，对人类健康至关重要。前期研究工作发现HEV感染引起肝损伤，肝细胞线粒体结构和功能紊乱是肝损伤发生的原因之一。线粒体结构和功能紊乱对细胞生命周期有重要调控作用。但在HEV感染机体的过程中，线粒体结构和功能紊乱引起肝细胞损伤的机制尚不明确。本项目拟在前期对HEV致肝损伤研究的基础上，将线粒体的结构与功能相结合，定位与定量相结合，以研究线粒体介导细胞凋亡信号通路、线粒体自噬信号通路PINK1/Parkin为切入点，寻找HEV感染的不同阶段，调节肝细胞线粒体自噬/凋亡平衡的关键因素；阐明HEV对肝细胞线粒体自噬/凋亡平衡的影响及分子机制，为临床制定HE治疗的靶向用药方案及针对HEV感染的切实有效的防控措施提供理论依据。

戊型肝炎（HE）是一种世界范围内流行的人畜共患病。近几年我国HE患病人数和死亡人数呈上升趋势，引起卫生部门与公众的重视。深入研究戊型肝炎病毒（HEV）的致病机制，进而有效防治HE，对人类健康至关重要。本研究基于前期研究基础，利用沙鼠感染HEV模型和HepG2/C3A-HEV感染性克隆细胞模型，通过体内外相结合的研究方式，从细胞生命周期调节的角度开展了HEV感染致肝细胞损伤的机制研究。研究结果证实，HEV感染可导致肝细胞线粒体自噬信号通路和凋亡通路激活，导致线粒体结构和功能的改变，引起氧化应激，进而造成肝细胞内环境发生异常变化，肝细胞损伤。本研究从一个新的视角阐述了HEV的致病机制，同时为进一步人类及动物预防和治疗戊型肝炎及靶向用药的方向提供了理论数据。