转录调节因子NcoR1抑制肝移植缺血再灌注损伤的作用和机制研究

肝移植缺血再灌注损伤是影响供肝功能的重要因素，缺血再灌注导致肝细胞ROS产生进而诱发其氧化应激损伤是重要的病理机制，肝细胞氧化应激及其诱导凋亡的分子调控机制是其中关键的科学问题。NcoR1是肝细胞核内重要的转录调节因子，申请人研究团队成员前期通过构建NcoR1肝细胞特异性敲除小鼠并发现，肝细胞NcoR1敲除促进脂质合成，但却抑制了肝细胞癌的发生发展。但是，肝细胞内NcoR1在肝脏缺血再灌注损伤中的功能和机制目前未知。据此，我们采用小鼠肝脏缺血再灌注损伤疾病模型，发现在肝细胞NcoR1敲除小鼠中，缺血再灌注损伤显著增强，ROS介导Nrf2信号活化进而诱导表达的氧化应激保护基因表达显著减弱。由此，本工作拟研究肝细胞核内转录调节因子NcoR1调控ROS效应信号通路诱导的氧化应激保护基因表达，进而抑制肝脏缺血再灌注损伤的功能和分子机制，以期为肝移植缺血再灌注损伤的临床干预提出新的潜在靶点。

Liver ischemia-reperfusion injury and the raised ROS in hepatocytes during liver transplantation significantly low the function of transplant liver, and the molecular regulatory mechanisms of oxidative stress is an important scientific question in liver transplantation. NcoR1 is an important nuclear transcriptional regulator, and we previously found that NcoR1 could improve lipid synthesis but promote hepatocarcinogenesis, using hepatocyte-specific NcoR1 knockout mice. However, the roles of NcoR1 in liver ischemia-reperfusion injury are still unknown up to know now. Hence, the liver ischemia-reperfusion injury mouse model was used, and we determined that hepatocyte-specific NcoR1 knockout significantly increased ischemia-reperfusion injury, and the ROS-induced Nrf2 activation and downstream anti-oxidant genes expression were suppressed. Thus, we intend to investigate the roles and underlying mechanisms of nuclear NcoR1 in the regulation of hepatic ischemia-reperfusion injury, so as to suggest new potential therapeutic targets for the intervene.