原发性胆汁性肝硬化中长链非编码RNA-GACAT1对肝内胆管细胞的调控机制研究

项目名称： 原发性胆汁性肝硬化中长链非编码RNA-GACAT1对肝内胆管细胞的调控机制研究

项目编号： No.81501398

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 张薇薇

作者单位： 中国人民解放军第二军医大学

项目金额： 18万元

中文摘要： 原发性胆汁性肝硬化（PBC）以胆管内进行性非化脓性炎症反应为特征，患者肝内胆管细胞（HiBEC）异常活化及过度凋亡是导致特异性肝损伤的重要因素。本研究组前期发现，PBC患者病变肝组织中长链非编码RNA-GACAT1表达显著增高、PTEN表达显著降低；经RNA pulldown技术证实GACAT1与PTEN蛋白相结合；过表达PTEN的HiBEC呈现LPS刺激后过度凋亡和异常活化。本项目拟解决以下关键问题：1.GACAT1通过PTEN调节HiBEC过度凋亡及其异常活化的调控机制；2.DNA甲基化和重要转录因子对GACAT1在HiBEC中的表达调控机制；3.利用PBC小鼠模型探讨调节GACAT1以治疗和预防PBC的可能性。本研究将有助于阐明PBC中HiBEC过度凋亡和异常活化的调控机制，为探讨免疫干预治疗PBC的新途径提供理论依据。

中文关键词： 原发性胆汁性肝硬化；长链非编码RNA；肝内胆管细胞

英文摘要： Primary biliary cirrhosis (PBC) is an autoimmune disease characterized by bile duct progressive non-suppurative inflammation. The intrahepatic bile duct cells (HiBEC) excessive apoptosis and abnormal activation has been proposed to account for the lesions be localizd on the bile duct. Our study found long-chain noncoding RNA-GACAT1 expression significantly increased and PTEN expression reduced in PBC patients' lesions liver tissue; GACAT1 binding with PTEN protein was found by RNA pulldown assay; stimulated by LPS, HiBECs which overexpression of PTEN to show excessive apoptosis and abnormal activation. This project intends to search for the following key issues: 1. the regulation mechanism of GACAT1 and PTEN in HiBEC apoptosis and abnormal activation; 2. the expression and regulation mechanism of DNA methylation and important transcription factors for GACAT1 in HiBEC; 3. using an mouse model to explore the possibility of regulating GACAT1 for the treatment and prevention of PBC. The above research, it will help us to clarify the mechanism of HiBEC excessive apoptosis and abnormal activation in PBC, and provide a theoretical basis to explore new ways of PBC immune intervention therapy.

英文关键词： Primary biliary cirrhosis;lncRNA;HiBEC