Mex3B调控TLR3信号在肠缺血再灌注肠损伤中的作用及机制

Intestinal ischemia reperfusion (I/R) injury is one of the severe events during perioperative period in patients. At present, the mechanism has not been completely revealed, also without effective strategy to prevent and treat it. In our pre-experiments, we found that both inflammatory response and apoptosis mediated by toll-like receptor 3 (TLR3) played an important role in I/R injury of lung and liver. In addition, the expression of TLR3 in intestinal mucosal tissue was significantly up-regulated after intestinal I/R. In combination with related literature report that Mex3B is associated with the activation and expression of TLR3, we put forward our hypothesis: Mex3B can regulate TLR3 signal thus mediate the development of intestinal I/R injury. In this study, firstly we intend to investigate the changes of Mex3B and TLR3 in intestinal mucosal tissue after intestinal I/R model built with wild type mice. Secondly, whether intestinal injury after intestinal I/R is mediated by Mex3B-TLR3-inflammation/apoptosis signaling pathways will be explored. Finally, through knockout mice and in vitro cell test, the role and mechanism of Mex3B and TLR3 in intestinal I/R injury will be verified. We speculate that the new mechanism and theory are helpful to provide new approaches and strategies for the prevention and treatment of intestinal I/R injury in clinical practice.

肠缺血再灌注（I/R）损伤是患者围术期发生的严重事件之一，目前其发生机制尚未完全明确，亦缺乏有效的防治策略。申请者前期研究发现Toll样受体3（TLR3）参与肺、肝等脏器I/R损伤的发生发展，且TLR3介导的炎症反应和细胞凋亡在肺和肝I/R损伤中发挥重要作用，进一步研究发现肠I/R后肠TLR3的表达明显上调，结合相关文献报道Mex3B与TLR3的激活和表达相关，申请者提出了Mex3B调控TLR3信号从而介导肠I/R肠损伤的科学假说。本项目拟通过观察野生型小鼠肠I/R后肠Mex3B及TLR3的表达变化，研究TLR3介导的炎症和凋亡机制在肠I/R肠损伤中的作用，并探讨Mex3B对TLR3表达的调控作用，最后通过敲基因小鼠和体外细胞实验，验证Mex3B和TLR3在肠I/R肠损伤中的作用及机制。本课题为深刻理解肠I/R肠损伤的发病机制，以及未来临床上寻找新的治疗靶点防治肠I/R肠损伤提供理论依据。

肠缺血/再灌注 (I/R)损伤是一种围术期常见但容易被忽视的病理生理现象，发生在许多临床事件中，包括严重感染、创伤、肠梗阻、休克、肠系膜动脉栓塞等疾患，以及腹主动脉瘤手术、心肺复苏、器官移植、体外循环下外科手术等。重要的是，肠I/R不仅导致肠道局部损害，而且因肠粘膜屏障破坏，肠内细菌、类毒素移位，导致全身炎症反应，从而启动肠外器官损伤链，导致多器官功能不全甚至衰竭，对患者的预后产生不利的影响。因此，研究肠I/R肠损伤机制及有效的防治策略，对改善急危重症患者及手术患者术后的转归具有重要的意义。. Toll 样受体（TLR）是天然免疫的重要组成成分，由三个区域构成，分别是胞质区、跨膜区及胞外区，其中胞外区是富含亮氨酸的结构域，主要功能是识别不同的病原体相关分子模式(PAMPs)或危险相关分子模式(DAMPs)，进而介导机体各种信号的转导。有关TLRs尤其是TLR3，目前研究最多的是其在免疫、炎症机制方面的作用。近年来，人们越来越关注TLR3在脏器I/R中的作用。研究报道在心、脑及肾等器官I/R中TLR3信号通路扮演重要的角色，表现为敲除TLR3基因均能不同程度的减轻动物脏器I/R损伤。基于此，本课题探讨了TLR3介导的炎症和凋亡信号通路在肠I/R肠损伤中的重要作用。. 本研究利用体外和体内实验，野生型和敲基因小鼠，系统的探讨了TLR3在肠I/R损伤中的表达、TLR3的表达与肠I/R后肠损伤的关系、TLR3信号介导的凋亡和炎性机制在肠I/R损伤中的作用以及exRNA/RNase与肠I/R后肠损伤之间的关系等一系列科学问题，结果表明TLR3介导的凋亡和炎性机制在肠I/R损伤中扮演重要的角色，抑制或敲除TLR3可不同程度上减轻肠I/R后肠损伤。同时，RNase围术期处理可显著降低肠I/R后肠损伤，以上研究为临床此类疾病的防治提供了新的思路和理论依据。