我们和其他研究证实：肝脏的缺血再灌注损伤（IR）过程中线粒体膜的脂质层存在明显的破坏，脂稳态作涉及肝脏缺血损伤的多方面，可能成为新的干预靶点。但是靶向性不强是目前肝保护剂难以奏效的重要原因。申请人曾所在的德国实验室首次设计合成了具有高度肝靶向的肝脏保护剂UDCA-LPE，前期研究显示了良好的抗炎性，抗凋亡，抗纤维化的作用。申请者前期的研究也显示出其对正常小鼠的肝IR的保护性作用。UDCA-LPE可以增加肝细胞内PC的含量，稳定细胞内脂质代谢。但是更深层的机制仍不清楚。申请者将从能量代谢着眼，细胞器水平以线粒体脂稳态的角度入手，分子水平以mTOR为中心，通过在不同水平调节PI3K/Akt/mTOR信号通路，来研究是否可以通过该通路来调控线粒体膜脂稳态，发挥其对肝脏IR干预的作用，并探讨新型靶向肝保护剂UDCA-LPE是否通过这种机制发挥其保护性作用。这为进一步研发高效靶向药物奠定基础。

We and other researchers have shown that the hepatic ischemia reperfusion injury (IR) has obvious damage to mitochondrial membrane lipid layer. Lipid homeostasis, which is involved in many aspects of liver ischemic injury, may become new targets for intervention. But poorly targeting is the major reason of ineffective role of hepatic protecting agent. Protective agent UDCA-LPE with Highly targeting to liver was synthesized in Germany laboratory where the applicant studied 3 years ago. Previous research on UDCA-LPE has shown a good anti-inflammatory, anti apoptosis, anti fibrosis effects. Applicant’s previous study also showed a protective effect on the normal mice liver IR. UDCA-LPE can increase the content of hepatic cells PC, stable intracellular lipid metabolism. But further mechanisms are still unclear. The applicant will focus on energy metabolism and mitochondrial lipid homeostasis. In the molecular level, the applicant will ,with mTOR as the center, regulate PI3K/Akt/mTOR signaling pathway in different levels to investigate the mechanisms of liver IR by PI3K/Akt/mTOR signaling pathway regulating mitochondrial membrane lipid homeostasis, and explore whether new targeted liver protective agents UDCA-LPE plays a protective role with this mechanism. This is to lay the foundation for further research and development of better liver protective agents.