LncTUG1调控AMPKα1甲基化促进巨噬细胞极化在腹主动脉瘤形成中的作用及机制

巨噬细胞极化失衡介导的慢性炎症是腹主动脉瘤（AAA）持续进展的关键因素，但巨噬细胞极化失衡的具体机制尚不清楚。我们前期研究发现：LncTUG1与AAA形成相关，并证实其参与巨噬细胞极化调节；进一步发现LncTUG1抑制AMPK转录与激活，这与DNA甲基酶（DNMT3B）介导的AMPKα1基因启动子甲基化有关。鉴于AMPK通路是调控巨噬细胞极化的经典通路，我们提出：LncTUG1通过招募DNMT3B促进AMPKα1基因甲基化并抑制其转录与激活，进而促进巨噬细胞M1型极化和炎症反应，导致AAA发生发展。本项目拟从动物、细胞和临床层面，首先明确LncTUG1参与AAA的发展；其次证实LncTUG1通过抑制AMPK影响巨噬细胞极化；然后阐明LncTUG1通过DNA甲基化调控AMPK的分子机制；最后探索LncTUG1在AAA中的临床转化意义。本项目研究成果有望为延缓AAA进展提供新思路和新靶点。

Chronic inflammation caused by macrophage polarization is a pathogenic factor in the progression of abdominal aortic aneurysm (AAA). However，the specific regulatory mechanisms remains to be elucidated. Our previous research found that LncTUG1 is related to the pathogenesis of AAA and participates in macrophage polarization regulation. We further found that LncTUG1 inhibits AMPK transcription and activation, which may be related to DNMT3B-mediated AMPKα1 gene promoter methylation. Since the AMPK pathway is a classic pathway that regulates macrophage polarization, we proposed the hypothesis: LncTUG1 promotes AMPKα1 gene methylation by recruiting DNMT3B and inhibits transcription and activation of AMPKα1, which in turn promotes macrophage polarization and inflammatory response, and ultimately induces AAA development. This project intends to conduct research from the animal, cell and clinical level. Firstly, we will verify that LncTUG1 participates in AAA development; secondly, we will confirm that LncTUG1 regulates macrophage polarization by inhibiting AMPK; and then we will clarify the epigenetic mechanism of LncTUG1 regulating AMPK through DNA methylation ; Finally, we will explore the clinical translational significance of LncTUG1 in AAA. This study is expected to provide new theories and therapeutic targets for the progression of AAA.