胆汁淤积时肝细胞内过量的胆酸导致肝损伤，并诱发肝脏产生自我保护的适应性反应，即胆酸代谢相关蛋白表达的适应性改变，但其机制尚不清楚。研究表明，炎症因子、核受体及其调控的胆酸代谢相关蛋白表达间密切相关；而炎症因子可激活MAPKs通路。我们在人胆汁淤积研究发现：上调的TNFα及其受体TNFRSF12A可能为该保护反应的关键因素，并伴MAPKs通路、核受体和胆酸代谢相关蛋白表达改变。因此，我们推测"TNFα-TNFRSF12A经MAPKs通路-调控核受体-改变胆汁酸代谢相关蛋白表达，使肝脏产生自我保护适应性反应。本项目应用基因芯片、siRNA、EMSA、Chip等技术，在体内、外研究：TNFα-TNFRSF12A能否激活MAPKs通路；进而调控相关核受体功能；最终改变胆酸代谢蛋白表达。本项目对阐明胆汁淤积时肝脏产生的自我保护适应性变化的分子机制，以及对临床胆汁淤积的治疗均具有重大意义。

The hepatic injuries by accumulation of toxic bile acids in hepatocytes could induce the adaptive and protective response in cholestasis, which results from the adaptive changes of bile acid related metabolic genes expression. However, the mechanism of this adaptive response is not clear so far. Recent study reported that there close relations existed among the inflammartory factors and its receptors, MAPKs signal pathway, nuclear receptors, and bile acid related metabolic proteins. Therefore, we hypothesized that: In cholestasis, TNFa activates MAPKs signal pathway by TNFRSF12A receptor, then regulates the expression of nuclear receptors, and finally leads to adaptive expression of bile acid related metabolic proteins to attenuate cholestatic liver injury.To prove above, we will apply Gene-chip,siRNA,EMSA,Chip assay etc. to investgate (in vitro and in vivo): Whether TNFa-TNFRSF12A activates MAPKs signal pathway, further changes the function of nuclear receptors, and finally controls the adaptive expression of bile acid related metabolic proteins. This study has crucial significance to clarify the molecular mechanism of hepatic adaptive and protective response in cholestasis and is promising to clinical therapy for cholestic liver diseases in future.