线粒体动态在肝纤维化贮脂细胞表型转化中的调控机制

项目名称： 线粒体动态在肝纤维化贮脂细胞表型转化中的调控机制

项目编号： No.81470864

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 张秀英

作者单位： 首都医科大学

项目金额： 73万元

中文摘要： 肝纤维化是各种慢性肝病发展到肝硬化必经的病理改变。贮脂细胞活化是肝纤维化发生、发展的关键环节。基于国内外研究现状和本实验室以往研究工作基础，我们提出如下假说：肝纤维化是由于各种原因产生的过量氧自由基，导致线粒体基因组DNA氧化应激损伤,线粒体动态调节失代偿, 引起贮脂细胞转化为肌成纤维细胞，造成ECM大量产生及过度沉积。本研究拟利用体内大鼠四氯化碳肝纤维化模型及体外肝贮脂细胞活化模型，探讨肝纤维化贮脂细胞表型转化过程中线粒体的异质性。应用高通量线粒体microRNA 芯片技术，对肝纤维化模型各期肝组织和肝贮脂细胞活化过程进行线粒体microRNA 谱检测，筛选并验证与肝纤维化贮脂细胞表型转化相关的线粒体microRNA及其对线粒体动态调控机制，从而为临床预防或治疗肝纤维化提供新思路。

中文关键词： 肝纤维化；肝贮脂细胞；线粒体；微小RNA

英文摘要： Live fibrosis is a consequence of continuous injury to the liver and results in cirrhosis. Activation of hepatic stellate cells (HSCs) plays a key role in the pathogenesis of liver fibrosis. We hypothesize that increased production of reactive oxygen species (ROS) caused by chronic liver injury may induce oxidation of mitochondrial DNA (mtDNA) reflected by mtDNA mutations, and may induce mitochondrial dysfunction and disorder of mitochondrial dynamics which may trigger HSCs transition to myofibroblasts and deposition of extracellular matrix. We propose to detect the mitochondrial heterogeneity in the process of HSCs transition using carbon tetrachloride (CCl4)-induced liver fibrosis in vivo and cultured HSCs in vitro, to compare the microRNA expression profiles during liver tissues fibrogenesis and the process of HSCs activation using microRNA microarray, and to screen and validate HSCs transition related mitochondrial microRNAs. Regulation of mitochondrial dynamics may offer a novel strategy for the provention and treatment of liver fibrosis.

英文关键词： liver fibrosis;hepatic stellate cells;mitochondrion;microRNA