内质网应激在急性肝衰竭肝再生障碍中的作用探讨

Impaired liver regeneration paly an important role in development and prognosis of patients with acute liver failure (ALF). However, the underlying mechanisms involved in the apoptosis and impaired liver regeneration in patients with ALF remain unclear. In our previous studies we have found that hepatocytes in mouse with ALF presented with sustained endoplasmic reticulum stress (ERS),sustained ERS of hepatocyte inhibits hepatocyte proliferation via down-regulation of c-Met expression. However, what roles of hepatocyte ERS play in the hepatocyte apoptosis and impaired liver regeneration in patients with ALF still remain unkown. In this study we plan to observe the correlation of hepatocyte apoptosis and liver regeneration with ERS of hepatocyte in mouse with ALF, then we plan to alleviate hepatocyte ERS by using prostaglandin E 1(PGE1)tauroursodeoxycholic acid(TUDCA)and 4-phenylbutyric acid (4-PBA) and observe its effects on hepatocyte apoptosis and liver regeneration in mouse with ALF, finally, we plan to use siRNA to inhibit the signal transduction of hepatocyte ERS and observe the prognosis of mouse with ALF. The objectives of this study are to explore the roles of hepatocyte ERS in the liver regeneration in mouse with ALF.

肝再生障碍是肝衰竭患者发病的重要环节，但是目前肝衰竭肝再生障碍的原因尚不清楚。我们前期研究发现急性肝衰竭小鼠残存肝细胞处于持续内质网应激（ERS）状态，内质网应激通过下调c-Met表达抑制人肝细胞株L02细胞生长和增殖。鉴于以上发现，我们提出的问题是：内质网应激通路诱导的肝细胞凋亡及肝再生障碍在急性肝衰竭的发病机制中起到什么作用？通过减轻肝细胞内质网应激能不能减轻急性肝衰竭肝细胞凋亡并促进肝细胞增殖？本研究1、通过药物诱导建立实验性急性肝衰竭小鼠模型，观察肝细胞ERS与肝再生的相关性；2、观察前列腺素E1（PGE1）、四苯基丁酸（4-PBA）及牛磺熊去氧胆酸（TUDCA）减轻肝细胞ERS后对肝细胞ERS通路及肝细胞凋亡及增殖的影响，3、用siRNA分别阻断肝细胞内质网应激通路后对小鼠生存率及肝细胞凋亡和再生的影响。旨在探讨肝细胞ERS在小鼠急性肝衰竭肝再生中的作用。

肝衰竭为多种病因引起的严重肝脏损伤，其发生、发展及其预后与肝细胞死亡及肝再生密切相关。肝再生障碍是肝衰竭患者发病的重要环节，但是目前肝衰竭肝再生障碍的原因尚不清楚。我们基于前期研究发现急性肝衰竭小鼠模型肝内存在持续内质网应激；在体外，内质网应激通过下调促肝细胞生长因子受体c-Met表达抑制肝细胞生长和增殖。提出探讨内质网应激对急性肝衰竭肝再生的作用及机制。我们通过急性肝衰竭/急性肝损伤小鼠模型及内质网应激肝细胞模型，探讨内质网应激对急性肝衰竭/急性肝损伤肝功能（胆红素代谢）、肝细胞死亡（凋亡及程序性坏死）、肝细胞细胞增殖的影响及机制。主要研究结论如下：①磷酸化eIF2α减轻急性肝损伤肝内内质网应激及肝细胞程序性坏死（SCI论文1篇，已接收）；②抑制eIF2α去磷酸化保护急性损伤肝细胞，减少肝细胞增殖（SCI论文1篇，已接收）；③内质网应激增加多药耐药蛋白2表达减轻急性肝损伤（SCI论文1篇，已接收）；④抑制eIF2α去磷酸化通过减轻急性肝损伤肝内内质网应激减少肝细胞凋亡（SCI论文1篇，已投稿）；⑤内质网应激信号通路的不协调激活可能参与肝病性别差异的形成过程（北图核心期刊1篇，已接收）。⑥内质网应激通过增强白介素6受体gp130蛋白翻译，负调节肝损伤（SCI论文1篇，已投稿）。共投递SCI论文5篇及中文北图核心期刊1篇，其中3篇SCI及1篇中文核心已被接收（均已标注资金支持）。授权发明1项专利，实用新型专利3项（均排名前三）。天晴肝病研究基金科研成果1项（中国肝炎防治资金会）。培养硕士研究生导师1名。后续研究获贵州省省级课题2项。