自噬在泡沫细胞发生和发展中的作用机制

项目名称： 自噬在泡沫细胞发生和发展中的作用机制

项目编号： No.81200213

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： 崔永春

作者单位： 中国医学科学院阜外心血管病医院

项目金额： 23万元

中文摘要： 自噬是巨噬细胞清除非必需物质的唯一生理过程，具有双向调节作用。最新资料表明，在动脉粥样硬化（AS）不同阶段斑块泡沫细胞中可见数量不等的自噬体，但其具体作用尚不明确。我们预实验发现，自噬诱导剂可减少氧化型低密度脂蛋白(ox-LDL)诱导形成的早期泡沫细胞内胆固醇含量。结合自噬在其他疾病中的作用机制，我们推测"自噬参与泡沫细胞发生和发展过程，并通过改变不同阶段泡沫细胞胆固醇含量和细胞命运发挥双向调节作用"。为证实上述假说，本研究拟首先利用ox-LDL诱导人单核细胞株THP-1和自噬相关基因5敲除（Atg5-/-）小鼠巨噬细胞形成的泡沫细胞来研究泡沫细胞发生、发展不同阶段自噬强度和细胞活力变化规律及其相互关系；然后在THP-1和apoE-/-小鼠两种体系中利用自噬诱导剂和抑制剂阐明自噬对不同阶段泡沫细胞胆固醇含量和细胞命运的影响，并探讨通过调控自噬防止泡沫细胞进展的可行性，为防治AS提供新思路。

中文关键词： 自噬；THP-1；基因敲除小鼠；泡沫细胞；动脉粥样硬化

英文摘要： Autophagy is the only process by which cell can get rid of unnecessary substance, and it has two-way regulations on cell fates. Recently, research has shown that there are a varying number of autophagosome existing in different stage of AS plaques, but it is still unclear whether it takes part in the development of foam cells. In one of our preliminary experiment, we found that autophagy inducers can reduce lipid droplets content in early foam cells induced by incubating with oxidized low-density lipoprotein (ox-LDL). Combined with the mechanisms of autophagy in other diseases, we assume that "autophagy may involve in occurrence and development of foam cells and play a two-way regulation by changing cholesterol content and cell fate of foam cells in different stages ". To confirm our hypothesis we will first use foam cells, induced by incubating macrophages derived from human monocyte cell line THP -1 and autophagy gene 5 knockout ( Atg5-/-) mouse with ox-LDL, to investigate the change patterns of autophagy and cell viability in foam cells of different stages and their relations. Then we will use autophagy inducers and inhibitors to explain the effects of autophagy on foam cell cholesterol content and cell fate in THP -1 macrophages and apoE knockout（apoE-/-）mice respectively, Exploring the feasibility of prev

英文关键词： Autophagy；THP-1；gene knockout mice；Foam Cell；Atherosclerosis