巨噬细胞通过MMP家族调控心肌缺血再灌注损伤的功能与机制研究

心肌缺血再灌注损伤（MIRI）及其过度修复引起的纤维化严重影响冠心病人和心脏手术患者的预后。巨噬细胞（Mø）是维持损伤/修复平衡、内环境稳态的重要免疫细胞。我们发现Mø募集与表型转换参与了MIRI发展，并率先发现人为增加M2b型Mø可缓解MIRI早期损伤及远期纤维化，改善心功能，提示Mø疗法是MIRI的潜在治疗手段。但Mø在MIRI的作用机制尚不清楚。Mø可分泌基质金属蛋白酶（MMP），可调控炎症、纤维化、心肌损伤等进程，前期发现MMP参与了Mø对MIRI的影响，是Mø发挥功能的重要分子，但目前缺乏Mø功能异质性与MMP作用网络的系统研究。因此，我们拟应用活体细胞示踪、流式细胞、蛋白组学、单细胞测序及体内外系列功能实验，鉴定出具有心肌保护作用的Mø群及其发挥关键作用的MMP群，在分子、细胞和整体水平系统研究Mø通过MMPs参与MIRI心肌保护的机制，为免疫细胞治疗MIRI奠定基础。

Cardiac fibrosis induced by myocardial ischemia-reperfusion injury (MIRI) and its excessive repair seriously affects the prognosis of patients with coronary heart disease and patients undergoing cardiac surgery. Macrophages (Mø) are important immune cells that maintain damage/repair balance and homeostasis. Previously we found that Mø recruitment and phenotypic change was observed in the development of MIRI. In addition, we first discovered that artificially up-regulated M2b Mø level can alleviate the early injury and long-term fibrosis of MIRI and improve the cardiac function, suggesting that Mø therapy is a potential treatment for MIRI. However, the mechanism of Mø's role in MIRI is still unknown. Mø can secrete matrix metalloproteinases (MMPs). MMPs regulate inflammation, fibrosis, and myocardial damage. MMPs are critical molecules which have been reported to be involved in the effect of Mø on MIRI. However, the functional heterogeneity of Mø and the systematic study of the interaction between Mø and MMP are largely lacking. In the present project, living cell tracking, flow cytometry, proteomics, single-cell sequencing, and a series of in vivo and in vitro functional experiments are used to screen the Mø and MMP subtypes which show cardioprotective effects, in order to further characterize the mechanism of MMPs-mediated protection of Mø against MIRI in cell-based models and in vivo animal models, ultimately laying a foundation for the immune cell treatment of MIRI.