Serp-2 调控apoptosis和pyroptosis 对肝脏缺血再灌注损伤的保护作用研究

项目名称： Serp-2 调控apoptosis和pyroptosis 对肝脏缺血再灌注损伤的保护作用研究

项目编号： No.81470791

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： 董家鸿

作者单位： 中国人民解放军总医院

项目金额： 73万元

中文摘要： 肝脏缺血再灌注损伤可导致肝细胞死亡。真核细胞程序性死亡包括apoptosis和pyroptosis等模式。caspase-8/-/9-/ -l0参与apoptosis信号传导。pyroptosis是一种依赖caspase-1的死亡模式。胞浆中的炎性体活化caspase-1后可加工分泌IL-1b和IL-18细胞因子，介导细胞发生肿胀破裂。Serp-2是Myxoma 病毒来源的蛋白酶抑制剂，抑制granzyme B，丝氨酸蛋白酶，半胱氨酸蛋白酶，caspases-1 和8。本研究首先建立标准化的动物模型, 在此基础上体外采用shRNA基因沉默方法和基因敲除小鼠在体外探讨Serp-2对肝脏缺血再灌注损伤的作用, 然后从apoptosis和pyroptosis两条路径探索Serp-2的作用机制, 最后研究Serp-2对肝门阻断后小肠淤血再通畅损伤的防治作用, 为Serp-2的临床应用奠定理论基础

中文关键词： 肝缺血再灌注损伤；Serp-2；细胞凋亡；pyroptosis

英文摘要： Liver ischemia-reperfusion (LIR) has clinical relevance to liver transplantation, partial hepatectomy. Studies suggesedt that apoptosis is the major patter of cell death after LIR. The eukaryotic cell' active and self-damage 'process is called programmed cell death (PCD), including apoptosis and pyroptosis. Caspase-8/-/9-/ -l0 are essential in cells for apoptosis. Pyroptosis is a caspase-1-dependent cell death showing similarities to apoptosis. The inflammasome refers to large multiprotein complexes that sense intracellular danger signals via NOD-like receptors (NLR). Inflammasome activation leads to auto-activation of the inactive pro-caspase-1 precursor into two subunits that form the active caspase-1, resulting in the cleavage of pro-IL-1b and pro-IL-18 into mature forms, accompanied by loss of plasma membrane integrity and lack of chromatin condensation. Serp-2 is an intracellular myxoma viral serpin that targets granzyme B, a serine protease,cysteine proteases and caspase-1 and 8. Therefore, in present study, the standard mice mode of LIR need to be established, and then to explore the effect of Serp-2 on LIR in vivo and vitro by using the ShRNA to silence the associated genes expression and gene knockout mice, after that to identify the mechanisms for Serp-2 protecting liver after LIR by two pathways of apoptosis and pyroptosis, finally to illustrate the preventive and treatment function of Serp-2 on intestine after congestion resulting from blockage of hepatic hillar.

英文关键词： liver ischemia reperfusion injury;Serp-2;apoptosis;pyroptosis