不稳定斑块破裂引起急性冠脉综合征（ACS）是心血管疾病致死致残的主要原因，其发生及破裂机制亟待阐明。课题组前期工作证实斑块的稳定性与IRGM显著相关，Irgm1可调控巨噬细胞的自噬、凋亡及炎症亚型的转化。本课题提出GTP酶Irgm1通过增强PI3K-AKT信号通路抑制巨噬细胞自噬，进而启动炎症，促进不稳定斑块的形成。申请人利用光学相干断层成像技术（OCT）、分子生物学、免疫学、动物学、细胞学及病理学等多种技术手段，在体内、外全面论证Irgm1通过PI3K-AKT信号通路对巨噬细胞自噬的调控，并利用OCT动态观察Irgm1对斑块稳定性的影响，明确其参与不稳定斑块易损性的分子机制及治疗靶点，填补国内外研究中针对Irgm1介导巨噬细胞自噬在不稳定斑块发生及破裂这一领域的空白。从临床、细胞及分子信号转导水平揭示Irgm1参与不稳定斑块发生及破裂的机制，为临床ACS防治策略提供新的思路。

Vulnerable plaque rupture induces acute coronary syndrome (ACS), which is the leading cause of morbidity and mortality in cardiovascular diseases. The development of vulnerable plaque is widely investigated, however, the mechanism is still unclear. Macrophage is one of the important innate immune cells that play a pivotal role in the stability of plaque. Our previous work showed the correlation between plaque stability and IRGM, and Irgm1 could regulate autophagy and apoptosis of macrophages. This study showed that the GTP enzyme Irgm1 inhibited macrophage autophagy by enhancing PI3K/AKT signaling pathway, which triggered the inflammatory responses and promoted the formation of unstable plaques. Optical coherence tomography (OCT), molecular, immunological,cellular, and pathological methods were utilized to confirm the role of Irgm1 in the regulation of macrophage autophagy in vivo and in vitro. The clinical OCT was used to dynamically observe the relationship between plaque stability and Irgm1 in patients, and explore the molecular mechanisms involved in the vulnerability of unstable plaque and the therapeutic targets. Our work will not only enrich the pathogenesis theory of ACS, but also provide a scientific guideline for the clinical treatment of ACS and a new insightinto the prevention and therapy.