慢性心理应激促进动脉粥样硬化病变的HMGB1/TLR4途径依赖机制

项目名称： 慢性心理应激促进动脉粥样硬化病变的HMGB1/TLR4途径依赖机制

项目编号： No.81500349

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 唐雅玲

作者单位： 南华大学

项目金额： 18万元

中文摘要： 我们前期研究发现：慢性心理应激加速动脉粥样硬化(As)发生、并增加TLR4与炎症因子表达；HGMB1/TLR4可能参与应激诱导的炎症反应。结合文献，我们提出慢性心理应激(以下简称应激)通过HMGB1激活TLR4而促进As发生发展的工作设想。本课题将观察应激As模型小鼠HMGB1、TLR4等的表达，以明确应激对HMGB1移位、释放与定位变化及HMGB1和TLR4相互作用的影响；探讨抗HMGB1中和抗体阻断对应激致As的抑制作用，以明确HMGB1是应激致As的关键信号分子；分析TLR4过表达与敲除对应激致炎症与As的影响，以证实应激通过TLR4途径促进As；探讨TLR4敲除与过表达对rHMGB1介导应激促As发生的影响，以阐明TLR4途径是HMGB1介导应激促As的重要信号级联。本项目的开展将揭示应激促进As病理进程的HMGB1/TLR4依赖机制，为As的防治拓展新思路和提供新靶点。

中文关键词： 慢性心理应激；动脉粥样硬化；高迁移率族蛋白B1；Toll样受体4；炎症

英文摘要： Our previous studies indicated that chronic psychological stress accelerated the development of atherosclerosis(As),and increased the expressions of TLR4 and inflammatory cytokines. Preliminary studies suggested HMGB1/TLR4 signaling cascade might be associated with inflammation induced by psychological stress. Combined with recent literatures, we hypothesize that the HMGB1/TLR4 pathway promotes the development and plaque instability of As induced by chronic psychological stress through inflammation responses.The effect of chronic psychological stress on HMGB1 translocation, release and localization will be visualized with immunofluorescent staining, and the effects on the expressions of HNGB1/TLR4 in mice will be detected by RT-PCR, western blot and immunohistochemical analyses, respectively. Furthermore, we use an anti-HMGB1 neutralizing monoclonal antibody to determine whether endogenous HMGB1 is a critical signaling molecules which contributes to atherosclerosis and inflammation in TLR4 wild-type mice induced by the psychological stress, and the influences on leision area, plaque instability, and proinflammatory mediators(which are downstream cytokines of HMGB1/TLR4) will be assessed by oil red O, immunohistochemistry, and western bolt, respectively. Finally, to confirm whether HMGB1-mediated inflammation responses and the development of As are via HMGB1-TLR4 signaling, TLR4 over-expression ApoE-/-mice,TLR4-/-/ApoE-/- mice and ApoE-/-mice will be pretreated with rHMGB1 and underwent the chronic psychological stress, and then the effects on the degree of As lesion and inflammatory cytokines levels will be assessed with the methods mentioned above. This study will provide novel insights into the pathogenesis of atherosclerosis induced by chronic psychological stress. Targeting HMGB1/TLR4 pathway may be a novel therapeutic approach to As-related diseases.

英文关键词： chronic psychological stress;atherosclerosis;high mobility group box 1;Toll-like receptor 4;inflammation