m6A甲基化酶METTL3通过miR-199a-3p/ABCA1途径促进动脉粥样硬化的作用及机制研究

Methyltransferase-like protein 3 (METTL3) is a key enzyme that mediates N6-methyladenosine modification (m6A), which is highly expressed in human atherosclerosis (As) plaques and macrophage-derived foam cells. Its exact effect on As, however, is unknown. Preliminary experiments and Bioinformatics analysis have shown Pri-miR-199a-3p has m6A modified site. Suppression of METTL3 can inhibit the expression of miR-199a-3p. miR-199a-3p can bind with the ATP binding cassette transporter A1(ABCA1). Based on the evidences above mentioned, we propose the hypothesis that the METTL3-mediated m6A modification upregulates the expression of miR-199a- 3p, targeting silencing of ABCA1, inhibiting cholesterol efflux, and promoting the occurrence of As. In this project, we will collect the clinical samples and establish the macrophage METTL3 specific knockout apoE-/- mice models to clarify the effect of METTL3 on macrophage lipid accumulation and As progress. Then, we would interfere or overexpress the METTL3- mediated m6A modification in macrophage to explore its role and mechanism in miR-199a-3p generation, ABCA1 expression and macrophage cholesterol efflux. This project is expected to reveal the role and mechanism of METTL3-mediated m6A modification in the progress of As from the perspective of epitranscriptomics, which would provide new ideas for the prevention of As.

甲基转移酶样蛋白3(METTL3)是介导m6A修饰的关键酶，在人动脉硬化(As)斑块和泡沫细胞中呈高表达，但在As中的作用未明。生物信息学分析和预实验显示，pri-miR-199a-3p存在m6A修饰位点，抑制METTL3可下调miR-199a-3p表达，miR-199a-3p靶向结合ABCA1。为此，我们提出：“METTL3介导的m6A修饰促进miR-199a-3p生成，靶向沉默ABCA1，抑制胆固醇流出，促进As”的假说。拟利用临床标本和巨噬细胞METTL3敲除的apoE-/-小鼠模型，明确METTL3/m6A修饰对巨噬细胞脂质蓄积和As斑块的影响；沉默或过表达巨噬细胞METTL3, 探讨其介导的m6A修饰对miR-199a-3p生成、ABCA1表达及细胞内胆固醇流出的影响。本项目有望从表观转录组学角度揭示METTL3介导的m6A修饰在As中的作用及机制，为As的防治提供新的思路。

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