肝脏缺血再灌注(IR)损伤长期制约着肝脏外科的发展，探索其有效治疗手段和作用机制一直是临床最迫切和有意义的任务。我们率先发表的阿片激动剂下调TLR4炎症通路具有非常理想肝保护作用的论文引起国内外广泛关注，近来我们还证实了β-arrestin既参与下调TLR4通路，其又能够被阿片激动剂诱导激活和膜易位。我们有理由相信β-arrestin既能桥接阿片与TLR4通路更是揭示阿片抗炎机制的关键分子。为了进一步阐明该分子在阿片下调TLR4炎症通路中扮演的角色及其从胞膜、胞浆至核内的详细信号传递过程，本课题拟采用转基因技术、RNA干扰技术和基因敲除动物模型，从整体动物、细胞和分子等多个水平观察β-arrestin在阿片激动剂减轻肝脏IR损伤中调控阿片和TLR4通路的关键作用靶位和机制。本研究将为进一步阐明肝IR损伤后炎症反应的免疫机制，并为临床实用性的阿片激动剂肝保护治疗提供重要的理论佐证和实验依据。

Hepatic ischemia reperfusion injury(HIRI) restricts the progress of liver surgery for a long period, to explore the effective treatment and mechanisms of HIRI are the most urgent and clinical meaningful task. We have demonstrated firstly that down regulation of TLR4 inflammatory pathways by opioid agonist conferred ideal hepatic protection, and this work has received wide spread attention. Recently we also confirmed that beta-arrestin participated both down regulation of TLR4 pathway and opioid agonist induced activation as well as translocation of membrane. We have reasons to believe that beta-arrestin can bridge opioid and TLR4 pathway for revealing opioid's anti-inflammatory mechanism as a key molecule. In order to further clarify the role of beta-arrestin on opioid inhibiting TLR4 inflammatory pathways and its signal processes from cell membrane cytoplasm to nucleus in detail, The present project will demonstrate the key target sites and mechanisms of beta-arrestin on opioid agonist reducing HIRI and its relations between opioid receptors and TLR4 pathways by using transgenic technology, RNA interference and animal models of gene knockout, these will also be viewed from the overall level of animal, cells and molecules. The present research will further clarify the immune mechanisms of inflammatory response after liver IR injury, and provide important theoretical evidence and experimental basis for the clinical practicability of opioid agonist's liver protection therapy.