巨细胞病毒通过激活血管内皮细胞HMGB1-RAGE/TLRs通路促进动脉粥样硬化形成的机制研究

项目名称： 巨细胞病毒通过激活血管内皮细胞HMGB1-RAGE/TLRs通路促进动脉粥样硬化形成的机制研究

项目编号： No.81500336

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： 吕亚丽

作者单位： 首都医科大学

项目金额： 18万元

中文摘要： 人巨细胞病毒（HCMV）感染是引起动脉粥样硬化（AS）的重要危险因素，但HCMV是如何触发和维持血管炎症反应并促进AS形成仍知之甚少。我们的预实验结果发现HCMV在感染的即刻早期（IE期）显著上调血管内皮细胞HMGB1、TLR4等分子的表达，而具体调控机制尚不清楚。为此，我们提出假说：HCMV通过激活HMGB1-RAGE/TLRs通路促进AS的形成。为了验证这一假说，我们将通过CMV感染血管内皮细胞和apoE基因敲除小鼠为模型，采用RT-PCR、Western blot、腺病毒载体转染、RNA干扰等手段，从分子、细胞、组织以及动物水平等多方面探讨CMV IE蛋白对HMGB1-RAGE/TLRs通路的调控机制，明确CMV通过HMGB1-RAGE/TLRs通路促进AS形成作用。本研究将从CMV IE蛋白调控HMGB1通路这个新视点为揭示AS的发生机制奠定基础，为AS的防治提供新的思路。

中文关键词： 动脉粥样硬化；巨细胞病毒；血管内皮细胞；即刻早期蛋白；血管炎症

英文摘要： Human cytomegalovirus (HCMV) infection is an important factor in atherosclerosis (AS), as in the report that HCMV-seropositive individuals have endothelial dysfunction and an increased atherosclerosis burden. But it does’t know clearly how HCMV is to trigger and maintain the vascular inflammation and promote the AS formation. Our previous researches showed that HCMV infection could improve the mRNA expression of HMGB1, TLR4 and TLR9 in endothelial cells in immediately early (IE) stage. However, its regulation mechanism is still not clear. Inspired by this, we proposed the hypothesis: HCMV infection accelerates the AS formation by activating the HMGB1-RAGE/TLRs signaling pathway. We will focus on this hypothesis to further explore regulation mechanism of viral IE proteins and HMGB1-RAGE/TLRs signaling pathway using by methods of real-time PCR, Western blot, RNAi, ect and models of endothelial cells and apoE knockout mice. The successful implementation of this project will reveal the mechanism of the AS foundation and provide a new therapeutic ideas for prevention and treatment of AS.

英文关键词： Atherosclerosis;Cytomegalovirus;Vascular Endothetial Cells;Immediate early protein;Vascular inflammation