GARP负向调控急性心肌梗死后心室重塑的免疫机制研究

Recent studies show that inflammatory immune response play a vital role in the development of ventricular remodeling after acute myocardial infraction (AMI). Glycoprotein A repetitions predominant(GARP) , a transmembrane protein expresed by activated Treg. GARP regulated the activation of Treg and secretion of TGF-β. Our preliminary study shows that the expression of GARP and level of TGF-β was impaired in patients with ACS. Pre-experiment indicates the expression of GARP was impaired in mice after AMI, and administrated sGARP can ameliorate the process of AMI after four weeks.The detailed mechanism of its regulation needs to be elucidate. In this project, GARP gene knockout AMI mice animal models will be used for: on one side administrated sGARP, and adoptive transfer GARP+T cells to the animal models, and to elucidate the role of GARP in the process of ventricular remodeling. On the other side to observe the biological effect of GARP+T cells on the cells associated with ventricular remodeling –cardiomyocytes, dendritic cells and macrophages. These exploratory studies will lead to a comprehensive understanding of the role of GARP in ventricular remodeling, and provide the theoretical and experimental basis for the development of targeted therapy in ventricular remodeling after AMI.

研究证实急性心肌梗死（AMI）后心室重塑过程中，免疫炎症反应起着重要作用。糖蛋白A为主的重复序列（GARP）主要表达于活化的Treg，其可调节Treg功能以及 TGF-β的分泌活化。我们研究表明，在ACS患者中GARP表达及TGF-β的分泌降低，且GARP+T细胞抑制效应性T细胞的增生受损；预实验发现AMI4周后小鼠外周血中CD4+GARP+ T淋巴细胞的表达降低，予以AMI小鼠可溶性GARP（sGARP）可以改善心室重塑进程，但机制尚未明了。本课题以GARP-/-小鼠作为AMI动物模型，通过予以外源性sGARP、过继转输GARP+T细胞，明确GARP在AMI后心室重塑过程中的作用。研究GARP+T细胞对心室重塑相关细胞（心肌细胞，树突状细胞和巨噬细胞）的影响。通过本课题研究，阐明GARP在心室重塑过程中的免疫学机制，完善心室重塑的免疫机制学说，为GARP作为新的干预靶点提供理论依据。

研究证实急性心肌梗死（AMI）后心室重塑过程中，免疫炎症反应起着重要作用。糖蛋白A为主的重复序列（GARP）主要表达于活化的Treg，其可调节Treg功能以及 TGF-β的分泌活化。我们研究表明，AMI4周后小鼠外周血中CD4+GARP+ T淋巴细胞的表达降低，并且予以AMI小鼠可溶性GARP（sGARP）可以改善心室重塑进程，其机制为减少小鼠心肌炎症反应，并且我们予以小鼠CD4+GARP+T细胞过继转输AMI小鼠体内，同样延缓了AMI后心室重塑。其机制为减少心梗部位的炎症，并调节了小鼠体内T细胞亚群的分群，同样体外实验证实了其可以抑制炎症因子分泌，通过本课题研究，阐明GARP在心室重塑过程中的免疫学机制，完善心室重塑的免疫机制学说，为GARP作为新的干预靶点提供理论依据。我们进一步探讨了小鼠I/R的机制研究，我们通过对同源盒转录反义基因间RNA（Hotair）的研究发现，其可以明显改善小鼠I/R后的心肌损伤，并且这种机制是通过AMPKα途径实现的，而且通过EZH2/miR-451/Cab39途径激活了AMPKα，从而达到减轻小鼠I/R损伤的机制，进一步为小鼠I/R损伤提供实验基础。