肝细胞损伤和代谢紊乱是肝病发生、发展的重要原因。前期研究发现：肝脏特异性敲除Sel1L基因小鼠（LKO）导致肝细胞内质网相关降解（ERAD）功能障碍，且表现为急性肝炎、代谢紊乱，最终发展为肝细胞癌，推测其原因可能是Sel1L敲除引起细胞内ERAD功能障碍，从而改变了内质网—线粒体间相关膜结构功能、影响了钙离子信号通路，导致线粒体代谢紊乱和形态功能改变。然而，其分子机理尚不清楚。本研究在前期研究基础上，以LKO小鼠和CRISPR技术敲除Sel1L基因的细胞系为平台，构建ERAD功能缺失模型，应用细胞器标记、电子显微镜等技术，筛选ERAD功能障碍影响内质网线粒体互作的关键通路和蛋白，且通过体内外实验进行验证。得到的结果将为深入理解ERAD功能缺失导致细胞器形态结构改变、及线粒体代谢紊乱和细胞损伤的分子机制提供依据，并为预防和治疗肝病新药的研发提供新的思路。

Hepatocyte injury and metabolic disorders have been shown to be responsible for the pathogenesis of liver disease. Through conditional gene-targeting in mice, we have previously showed that liver-Sel1L knockout mice developed nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) with dysfunction of endoplasmic reticulum (ER)-associated degradation (ERAD) system and metabolic disorder. However, the molecular mechanism is incompletely understood. Base on the model of ERAD dysfunction, the overall goal of the current project is to investigate the regulatory roles of ERAD dysfunction in the control of mitochondria-associated ER membranes (MAMs) and Ca2+ signal pathway factor, which are two key factors that cause mitochondrial damage and metabolic disorders. To achieve this research goal, our experimental strategy is to generate and analyze the morphological and functional phenotypes of mice and cell line with hepatocyte-specific deletion of the Sel1L gene. Understanding the molecular mechanisms underlying hepatocyte injury would facilitate the development of novel drugs for the treatment of liver diseases.