DFMG调控miR-425-5p抑制巨噬细胞炎症反应抗AS的作用及机制研究

动脉粥样硬化（AS）是严重危害人类健康的疾病，靶向巨噬细胞炎症反应已成为抗AS药物研发的重要策略。拥有自主知识产权的新型活性化合物DFMG（专利号：ZL200710104389.4）具有体内外抗AS作用，但机制尚未明确。TLR4是炎症反应的重要调节因子并受miRNA调控，而DNA甲基化与去甲基化又是调控miRNA的重要机制。我们前期工作发现DFMG能缓解巨噬细胞炎症反应，且miR-425-5p在此过程中发挥重要作用。基于此，我们拟开展以下研究内容：1）阐明DFMG通过上调miR-425-5p靶向抑制TLR4抗巨噬细胞炎症反应的机制；2）研究miR-425-5p在巨噬细胞炎症反应中被DNA甲基化沉默以及被DFMG通过TET1介导的DNA去甲基化重新活化表达的机制。本项目将揭示巨噬细胞炎症反应的病理新机制及DFMG抗AS的全新药理作用机制，为防治AS新药的研发提供科学依据。

Atherosclerosis (AS) is a disease that seriously endangers human health. Targeting the inflammatory response of macrophages has become an important strategy for the development of anti-AS medicine. DFMG (patent number: ZL200710104389.4), a new type of active compound with independent intellectual property rights, has anti-AS effects in vivo and in vitro, but the mechanism is not yet clear. TLR4 is an important regulator of inflammatory response and is regulated by miRNA. DNA methylation and demethylation are also important mechanisms for regulating miRNA. Our previous work found that DFMG can alleviate the inflammatory response of macrophages, and miR-425-5p plays an important role in this process. Based on this, we intend to carry out the following research contents: i) to elucidate the pharmacological mechanism of DFMG inhibiting macrophage inflammatory response by regulating miR-425-5p/TLR4 axis; ii) to investigate the mechanism of miR-425-5p silenced by DNA methylation in macrophage inflammatory response and reactivated by DFMG through TET1-mediated DNA demethylation. This project will reveal the new pathological mechanism of macrophage inflammatory response and the new pharmacological mechanism of DFMG against AS, so as to provide a scientific basis for the development of new anti-AS medicine.