Dectin-2/CCTη信号轴在心肌梗死后心室重构中的作用及机制探究

固有免疫机制介入心肌梗死后心室重构/心力衰竭的发生发展过程日渐成为热点。本课题组在前期研究中发现，Dectin-2作为一种重要的固有免疫识别受体PPRs，具有通过介导炎症/凋亡相关反应并参与心肌梗死后心室重构的潜能：特异性敲除Dectin-2可显著改善心肌梗死小鼠的心脏结构和心功能水平；激活的Dectin-2可诱导CCT蛋白家族的CCTη亚单位表达上调，导致CCT蛋白构象改变并与Dectin-2胞内伴侣FcRγ段结合，介导下游炎症通路、凋亡因子的表达并促进心肌纤维化，加重心肌梗死后心室重构的病理过程。因此，本课题组后续将拟应用基因修饰小鼠为模型，通过体内/体外实验全面探讨Dectin-2/CCTη信号轴在心肌梗死后心室重构中的作用，探寻Dectin-2对CCTη的特异性磷酸化修饰位点，阐明相关机制，为心肌梗死患者阻断心肌重构、维持心脏功能和预防心力衰竭提供新的治疗靶点和手段。

It has been recognized that innate immunity is involved in the pathophysiological processes of myocardial ischaemic injury. Dendritic cell-associated lectin-2 (Dectin-2), the specific pattern-recognition receptor in the innate immunity, plays a pivotal role in apoptosis, immunity and inflammation. To date, the causal relationship between Dectin-2 and cardiac remodelling after myocardial infarction（MI）remains largely unexplored. In our previous study, we observed several clues as follows: (1) The expression levels of dectin-2 in post-MI heart were up-regulated compared with WT control mice. (2) Compared with WT controls, dectin-2-KO mice developed smaller infarct sizes and preserved more left ventricle (LV) function after MI. Significantly, dectin-2-KO hearts had less cardiomyocyte apoptosis and inflammatory cell infiltration. (3) Attenuated LV remodelling was also discovered in the KO post-MI hearts, with reduced cardiac hypertrophy and fibrosis as well. (4) Mechanistically, our data revealed that dectin-2 acts as an inducer of CCT(chaperon containing TCP1)-η expression and mediates post-MI remodelling via activation of the CCTη signalling pathway. Taken together, it has been speculated that Dectin-2/CCTη pathway may play a detrimental role on cardiac remodelling after MI.In the following study, further in vitro and in vivo experiments will ascertain the specific phosphorylation site of CCTη and illuminate the functional role of Dectin-2/CCTη pathway in the pathophysiological processes of cardiac remodelling after MI. Our research will lay down the basis for the specific mechanism of cardiac remodelling and explore a novel therapeutic target to intervene heart failure after MI.