miR-33a在NF-κB促巨噬细胞脂质蓄积中的作用及机制

项目名称： miR-33a在NF-κB促巨噬细胞脂质蓄积中的作用及机制

项目编号： No.81200218

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： 赵国军

作者单位： 南华大学

项目金额： 23万元

中文摘要： miR-33a在巨噬细胞脂质蓄积中起重要作用，但细胞内调控其表达的机制尚未阐明。我们使用生物信息学分析发现miR-33a的宿主基因SREBP-2启动子区恰含有NF-κB的DNA结合元件，预实验显示NF-κB活化可促进miR-33a表达，因此提出miR-33a受NF-κB转录调控从而促进巨噬细胞脂质蓄积的学术思想。为此本项目拟在确认NF-κB促进miR-33a表达的基础上，采用报告基因分析、EMSA和ChIP等方法深入研究NF-κB调控miR-33a表达的分子机制；通过miR-33a的过表达与内源性沉默，明确其在NF-κB促进脂质蓄积中的作用；建立动脉粥样硬化(As)动物模型，整体上评价NF-κB对miR-33a的调控作用。本项目将阐明miR-33a在NF-κB促巨噬细胞脂质蓄积中的作用及机制，为As的病理生理机制提供新的研究方向，为以miR-33a为靶点防治As提供新的实验依据和理论基础。

中文关键词： 微小RNA-33a；核因子-kappa B；三磷酸腺苷结合盒A1；固醇调节元件结合蛋白-2；动脉粥样硬化

英文摘要： miR-33a plays important roles in lipid accumulation in macrophages, but the mechanisms that regulate the expression of miR-33a are still not clear. Because miR-33a is coexpressed with its host gene, SREBP-2, we examined the promoter of SREBP-2 using bioinformatics analysis, and found that SREBP-2 promoter includs NF-κB DNA-binding elements. Our preliminary experiments also exhibited that NF-κB activation could up-regulate the expression of miR-33a. Thus we bring up a creative scientific idea that miR-33a is regulated by NF-κB and thereby promoting lipid accumulation in macrophages. Based on the confirmation of NF-κB activation promoting the expression of miR-33a, the project will investigate more deeply the molecular mechanisms of NF-κB regulating miR-33a by luciferase reporter gene assay, EMSA and ChIP etc. Then we will explore the effects of miR-33a on NF-κB promoting lipid accumulation through over expression or endogenous silence it in macrophages. Finally, we evaluate the regulatory role of NF-κB in miR-33a expression at systematic level through establishment of atherosclerosis animal model. In summary, our study will clarify the important role of miR-33a in NF-κB promoting macrophage lipid accumulation, and elucidate the regulatory mechanisms of miR-33a in vivo. These findings will provide new thoughts for

英文关键词： MiR-33a；NF-κB；ABCA1；SREBP-2；atherosclerosis