SK-2,S1P及内质网应激在脂肪肝缺血再灌注损伤及原发性肝无功中机制研究

脂肪肝供肝导致移植后原发性肝无功的发生，从而加重供肝的短缺。S1P在脂肪肝中表达明显增加并导致肝脏损伤及炎症.我们的前期工作表明在肝缺血再灌注过程中，内质网应激信号通路激活，SK-2及S1P明显增加，导致线粒体去极化及线粒体通透性改变（MPT）发生，激活后续的炎症信号通路。我们推测在脂肪肝的缺血再灌注时，内质网应激启动UPR，通过调控下游多种信号通路PERK,IRE1α及ATF-6等，导致SK2及S1P的表达增加，而S1P通过与其受体结合，活化Ｇ蛋白偶联调节的信号通路，从而导致线粒体去极化及MPT，肝细胞坏死凋亡及炎症链式反应通路激活。本课题通过建立脂肪肝缺血再灌注、肝移植模型及肝细胞缺氧再氧化模型，采用ＳＫ２基因敲除技术、SiRNA技术及活体动物体外多光子显像技术，来研究内质网应激、SK2及S1P在脂肪肝缺血再灌注损伤及原发性肝无功能中的机制。

Donor liver steatosis contributes to the process of primary non-function inliver transplantation. It worsens the problem of organ shortage. In the disease of fatty liver, S1P expression increases and also causes liver injury and inflammation . Our preliminary work has demonstrated that Endoplasmic Reticulum Stress pathway activates SK2 and the expression of SK2 and S1P increase in the process of hepatic ischemia reperfusion injury. It causes mitochondrial depolarization and mitochondrial permeability transition. It activates inflammatory chain-reaction signal pathway. In this project, we establish fatty liver ischemia-reperfusion injury 、liver transplant and hepatocyte anoxia re-oxygenation modell. We use SK2 gene knockout, Si-RNA and Intra-vital Multi-photon Microscopy techniques to explore the role of ER Stress, SK2 and S1P in the process of ischemia reperfusion injury and primary non-function of fatty liver.