Tim3调控定居巨噬细胞减轻AMI心肌损伤的机制研究

心脏定居巨噬细胞（cardiac resident macrophages, rCMΦ）对急性心梗(AMI)的损伤与修复有至关重要的影响，对其关键调控分子的发现与机制探究具有重要科学意义。我们研究发现：新型免疫检查点分子Tim3过表达小鼠AMI损伤轻微；Tim3敲除及sTim3蛋白阻断处理的小鼠AMI损伤加重；Tim3在MΦ上表达显著高于心肌与内皮细胞。而Tim3调控rCMΦ减轻AMI心肌损伤的机制尚需探究。本项目拟在AMI动物模型中研究：①Tim3在心脏MΦ上的表达特征及对其群体构成的影响；②Tim3对rCMΦ驱动的外周MΦ浸润与极化的影响及其在调控rCMΦ自身增殖、吞噬及细胞因子分泌功能中的作用；③靶向Tim3进行激动剂干预及rCMΦ移植改善AMI损伤的效果。本研究有望发现Tim3在心脏免疫中的新功能，揭示Tim3调控rCMΦ功能减轻AMI损伤的新机制。

Cardiac resident macrophages (rCMΦ) play an important role in the injury and repair during acute myocardial infarction (AMI), but its key regulatory molecules and mechanisms need to be explored. Tim3 is an important immune checkpoint molecule, but its effect on cardiac immune microenvironment after AMI has not been reported. In our previous study, we found for the first time that AMI damage was mild in Tim3 overexpression mice, while AMI was aggravated in mice treated with Tim3 knockout and sTim3 protein block. The expression of Tim3 in MΦ was significantly higher than that in myocardium and endothelial cells. The purpose of this study was to study: 1 The expression characteristics of Tim3 in cardiac MΦ and its effect on the population composition of AMI; 2 The effect of Tim3 on the infiltration and polarization of peripheral MΦ driven by rCMΦ, and its relationship with the regulation of proliferation, phagocytosis and cytokine secretion of rCMΦ. 3 The effect of targeted Tim3 agonist intervention and rCMΦ transplantation to improve AMI injury. This study is expected to discover the physiological function of Tim3 in cardiac immune regulation, reveal the new mechanism of Tim3 regulating rCMΦ function to reduce AMI damage, and provide a new theoretical basis for the prevention and treatment of AMI.