HIF-1α对动脉粥样硬化斑块巨噬细胞自噬作用及生物学效应的影响

项目名称： HIF-1α对动脉粥样硬化斑块巨噬细胞自噬作用及生物学效应的影响

项目编号： No.81200220

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学一处

项目作者： 万静

作者单位： 武汉大学

项目金额： 23万元

中文摘要： 自噬作用是细胞的一种生理性修复现象。我们前期试验证实动脉粥样硬化斑块局部存在缺氧，发现缺氧对巨噬细胞自噬作用的影响有可能与HIF-1α的表达相关。有研究表明mTORC1的抑制可以诱导巨噬细胞自噬作用，对细胞进行保护，并加速其转变成泡沫细胞，是斑块形成的一个重要因素。我们认为HIF-1α是通过抑制mTORC1诱导巨噬细胞自噬作用，PPAR-γ作为重要的核受体，很可能是其下游信号转导途径，因此提出缺氧可能通过HIF-1α- mTORC1-PPAR-γ途径影响巨噬细胞的自噬及生物学效应的假说。本项目拟通过缺氧、转染HIF-1α腺病毒及siRNA干扰，改变细胞内HIF-1α的表达，观察apoE-/-小鼠BMDM自噬作用、迁移及泡沫细胞形成，以发现缺氧、HIF-1α，mTORC1及PPAR-γ与粥样斑块形成之间的内在联系；并探索规则氧疗对高脂饮食喂养apoE-/-小鼠模型动脉粥样硬化斑块形成的影响，

中文关键词： 缺氧诱导因子；哺乳动物雷帕霉素标靶复合物-1；巨噬细胞；自噬作用；动脉粥样硬化

英文摘要： Autophagy is a physiological cell repair process. Our previous studies demonstrated that there was a hypoxia microenvironment in the atherosclerosis plaques, and we further showed that hypoxia caused the expression of HIF-1α, WHICH MIGHT LEAD to the induction of autophagy of macrophages. It has been reported that the inhibition of mTORC1 expression induced autophagy of macrophages, led the formation of foam cells from macrophages, and accelerated the formation of the plague. PPAR-γ, a nuclear receptor, probably plays the role as a downstream signal factor of mTORC1. We hypothesize that HIF-1αinduces the autophagy of macrophages by inhibiting the expression of mTORC1 signals and its down-stream regulator PPAR-γ. Therefore, we plan to overexpress HIF-1α using adenovirus and silence its expression using siRNA in BMDM from apoE-/- mice. By using these strategies, we seek to study the effect of HIF-1αon autophagy, the formation of foam cell in the microenvironment of atherosclerosis. Furthermore, we plan to induce hypoxia in the mice to study the relationship between hypoxia, HIF-1αinduction, mTORC1-PPAR-γsignaling pathway regulation, and the formation of the plague. Eventually, we plan to study the effect of long term oxygen therapy on AS formation using apoE-/- mice with high cholesterol diet as the animal model to

英文关键词： Hypoxia inducing factor-1α；mTORC1；Macrophage；Autopagy；Atherosclerosis