microRNA-185介导的胆固醇代谢调控机制研究

项目名称： microRNA-185介导的胆固醇代谢调控机制研究

项目编号： No.81473214

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 王丽

作者单位： 中国医学科学院医药生物技术研究所

项目金额： 65万元

中文摘要： 动脉粥样硬化是心血管疾病的主要病理基础，与脂质代谢紊乱密切相关，LDL受体（LDLR）途径和HDL介导的胆固醇逆转运（RCT）途径在脂代谢过程中发挥着重要作用。由于多靶、微调、功能冗余等特性，miRNA在基因调控网络中发挥了复杂而精细的调节作用。本课题组前期工作中发现miR-185可调控HDL受体SR-BI表达及其在RCT中的功能，进而发现miR-185抑制剂可降低小鼠血浆总胆固醇及LDL胆固醇水平，并初步证实miR-185对LDLR以及其调控相关的转录因子（TFs）和RNA结合蛋白（RBPs）的调节作用。本项目拟在分子、细胞及动物水平，继续探究miR-185对LDLR表达的直接调节作用及机制，并通过研究miR-185与TFs或RBPs组成的调控单元，解析miR-185介导的脂代谢综合调控网络，研究结果将可能为新型调血脂药物的研发提供新的靶点和思路，具有重要的科学意义和应用价值。

中文关键词： 动脉粥样硬化；胆固醇代谢；microRNA；LDLR；基因调控

英文摘要： Atherosclerosis, the main cause of cardiovascular disease, is associated closely with lipid disorders. Both LDL receptor (LDLR) pathway and reverse cholesterol transport (RCT) pathway mediated by HDL play an important role in lipid metabolism. So far, LDLR regulation remains the main target of anti-atherosclerosis drug discovery. MicroRNAs (miRNAs) are hairpin-derived RNAs of about 20-24 nucleotides long, which posttranscriptionally repress the expression of target genes usually by binding to the 3'UTR of their mRNAs. One miRNA may regulate several genes, while one single gene may be regulated by several miRNAs at the same time, which is known as multi-targets, fine tuning, functional redundancy properties of miRNA regulatory mechanism, implicating a complex and highly orchestrated mode of gene regulation. In our previous study, miR-185 was found to regulate the expression of HDL receptor (SR-BI) and SR-BI mediated HDL-C selective uptake in RCT pathway. The following research indicated that the plasma total and LDL cholesterol of ApoE-KO mice were both decreased by miR-185 inhibitor (anti-miR-185). Then we found that miR-185 regulated the expression of LDLR, as well as some transcriptional factors (TFs) and RNA binding proteins (RBPs) relative to LDLR regulation. Based on this, we are going to further investigate the regulatory mechanism of miR-185 on LDLR expression by directly binding to its 3'UTR, and explore miR-185 mediated-TFs or RBPs involved cholesterol regulatory network. The results obtained in this study may provide new insights into the regulatory mechanism of lipid metabolism, and furthermore, potential novel targets for lipid-regulating agent discovery.

英文关键词： Atherosclerosis;Cholesterol metabolism;microRNA;LDLR;gene regulation