自噬，凋亡，还是坏死？TLR4通路介导急性胰腺炎细胞死亡调控机制研究

项目名称： 自噬，凋亡，还是坏死？TLR4通路介导急性胰腺炎细胞死亡调控机制研究

项目编号： No.81470886

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： 李园

作者单位： 四川大学

项目金额： 73万元

中文摘要： 重症急性胰腺炎(SAP)病死率仍居高不下,是世界范围内的医学难题。急性胰腺炎(AP)的严重程度与细胞死亡方式相关,调控胰腺细胞死亡方式将影响AP的发展与转归。自噬、凋亡与坏死作为特征性的细胞死亡方式均参与了AP病程,但决定AP细胞死亡方式取向的调控机制,以及影响AP转归的机理不明。申请者基于前期发现：TLR4作为炎症反应核心蛋白,其缺失与野生小鼠株在诱导AP后,胰腺细胞凋亡坏死存在显著差异；在特定时点，胰腺腺泡细胞超微结构中可见大量类似自噬空泡化的结构改变,提出TLR4可能参与AP病程中多种细胞死亡方式的取向调控。本课题以TLR4信号介导自噬,凋亡,坏死为切入点,联合采用多株炎症-细胞死亡通路关键分子基因缺失小鼠及基因稳定沉默细胞系,深入探讨AP中TLR4信号通路与胰腺细胞死亡的调控规律及对AP病程影响，结果将对AP发病机理提出新的认识，并为AP/SAP的预防及治疗提供转化思路和实验依据。

中文关键词： 急性胰腺炎；Toll样受体4；自噬；凋亡；坏死

英文摘要： The mortality of severe acute pancreatitis (SAP) remains high and challenging doctors worldwide. The severity of acute pancreatitis is paralleled with the predominance of a given type of cell death, and inflammatory attack in AP could be alleviated by regulating the different types of cell death development. Autophagy, apoptosis and necrosis, all of which are typical cell death involved in AP, but the potential regulatory mechanism between the three and the relation and effector for the prognosis of AP remain unclear. Based on our preliminary results, which evidenced pancreatic apoptosis was significantly different between mice with or without the expression of Toll like receptor 4 (TLR4), and a big amount of autophagy-like vesicles could be detected in cytoplasm at specific time points of AP, we proposed that TLR4 might potentially be involved in the regulation of three types of cell death in AP. This project focuses on the potential role of TLR4 in regulating autophagy, apoptosis and necrosis in the development of AP, with comprehensively apply multiple mice strains and multiple stable cell lines with key regulatory gene of inflammatory or cell death pathways knockout/knockdown, to intensively study and analyze the role of TLR4 signaling in possible predisposing or regulating different types of cell deaths in the development of AP. This study will provide new insights for understanding the pathogenesis of AP, and provide research evidences for further translational diagnosis and treatment of AP.

英文关键词： acute pancreatitis;toll like receptor 4;autophagy;apoptosis;necrosis