基于FMO3基因多态性联合CT用于蒙古族动脉粥样硬化风险评估的作用和机制研究

The synthesis of TMAO by FMO3 is one of the most important mechanisms of the pathogenesis of atherosclerosis (AS) after gut microbiota degrading high-fat diet. The model integrating gene information and CT imaging data will provide a reference for early warning of AS. In the previouswork, the rs41272509 [A/G] locus in the 3'UTR region of FMO3 was found to be associated with the risk of AS, which was located at the binding site of miR-340-5p and FMO3 mRNA,affecting FMO3 expression. Thus we propose the following scientific hypothesis: rs41272509 regulates FMO3 enzyme expression and activitysite by affecting miR-340-5p and FMO3 mRNA binding, involved in choline-TMA-TMAO metabolic pathway and affecting cholesterol metabolism and macrophage activity, and thus participate in the AS The development. The project will explore the role and mechanism of rs41272509 on the expression and activity of FMO3 through miR-340-5p at the cellular and animal level and integrate the CT imaging data with the blood data of miR-340-5p, rs41272509 and TMAO content for the assessment of Mongolia population suffering from the risk of AS model to reveal the pathogenesis of AS and risk warning provide new ideas.

肠道微生物降解高脂饮食后FMO3酶合成TMAO是动脉粥样硬化(AS）发病重要机制，整合了基因信息和CT影像学数据的模型将为AS早期风险预警提供参考。项目前期发现位于FMO3 3’UTR区的rs41272509[A/G]位点与AS风险相关，该位点位于miR-340-5p与FMO3 mRNA的结合位置，影响FMO3的表达水平。假设rs41272509位点通过影响miR-340-5p与FMO3 mRNA结合从而调节FMO3酶表达和活性，参与胆碱-TMA-TMAO代谢途径，影响胆固醇代谢和巨噬细胞活性，从而参与AS发生发展过程。项目将从细胞和动物层次探索rs41272509通过miR-340-5p影响FMO3表达和活性的作用与机制，并整合CT数据与miR-340-5p、rs41272509和TMAO含量的血液数据建立用于评估蒙古族人群罹患AS风险的综合模型，为揭示AS发病机制和风险预警提供新思路。

动脉粥样硬化是常见的心血管系统疾病之一，在世界范围内有着较高的发病率和死亡率，临床危害极大。据报道环状RNA和微小RNA在AS的发生和发展中发挥着关键作用，因此揭示其在动脉粥样硬化发病中的作用和机制将有助于建立新的发病风险预测模型并为开发干预药物提供新思路和靶点。本研究旨在探讨circRNAs调节AS炎症的潜在机制，寻找鉴定AS中差异表达miRNAs的生物学效应。我们的研究表明 circRNA_0050486在 oxLDL 诱导的 THP-1 巨噬细胞中上调，circRNA_0050486 的敲低通过靶向 miR-1270 抑制炎症和细胞凋亡；我们的研究还发现，miR-148a-3p 通过靶向 CNTN4在AS中发挥作用，miR-148a-3p 通过靶向 THP-1 巨噬细胞中的 CNTN4 来抑制 oxLDL 诱导的细胞凋亡和炎症。这一发现可能为动脉粥样硬化提供一个潜在的治疗靶点，在AS防治中具有重要科学意义，具有比较广阔的临床应用前景。