MST1通过脂质代谢产物LTB4调控心肌梗死后炎症修复的分子机制研究

心肌梗死（MI）引起的局部急性炎症反应是影响心肌损伤修复的关键。炎症过程中巨噬细胞浸润及不同类型脂质代谢产物的平衡对调节炎症反应进展与清除发挥重要作用。蛋白激酶MST1是调控免疫系统巨噬细胞炎症反应的重要调节因子，然而其在MI后心肌损伤修复中的机制尚未阐明。申请者预实验结果发现在MI后第7天小鼠巨噬细胞中MST1表达显著增加；敲除巨噬细胞MST1促进了促炎型脂质代谢产物LTB4的分泌，同时抑制巨噬细胞吞噬功能，不利于MI后的心脏修复。据此提出假说：巨噬细胞MST1通过抑制LTB4的合成介导巨噬细胞吞噬功能，从而保护MI后的心脏功能。本研究将建立MI小鼠模型，通过流式细胞术、心动超声等方法分析MST1缺失对MI后巨噬细胞功能和心脏组织修复的影响；利用质谱、免疫共沉淀、蛋白质组学等方法对MST1抑制LTB4合成进行分子机制探讨，以期为MI靶向治疗提供新思路。

The local inflammatory response in myocardial infarction is a key point affecting myocardial repair. Macrophage infiltration and the balance of diverse lipid mediators during acute inflammation regulate inflammatory response and tissue resolution. MST1 is considered to be an important regulator of macrophage inflammation in immune diseases, however, the specific mechanism of macrophage MST1 after MI has not yet been elucidated. In the preliminary study, macrophage MST1 increased significantly 7 days post-MI. MST1 depletion increased LTB4 production and decreased macrophage efferocytosis, which is not conducive to heart repair. On the basis of our findings, the hypothesis of the current project is that MST1 mediates macrophage function by inhibiting LTB4 synthesis, thereby protecting heart function after MI. This study will establish an MI mouse model and analyze the effect of MST1 loss on macrophage function and tissue repair by flow cytometry, echocardiography, et al. Using LC/MS, CO-IP, proteomics, et al to explore the molecular mechanism of MST1 inhibiting LTB4 synthesis. Within this study, we anticipate to explore a novel therapeutic target of myocardial infarction.