TRPV1通过CaMKII-AMPK/NLRP3通路调控巨噬细胞破骨化在腹主动脉瘤中的作用机制研究

炎症反应是腹主动脉瘤发生发展的关键因素，其中巨噬细胞表型转化发挥着重要的作用。近期有文献提示巨噬细胞破骨样转化与腹主动脉瘤进展相关，但其调控机制及功能改变尚不清楚。TRPV1作为一种Ca2+离子通道，在骨组织中调控破骨细胞形成，申请者前期实验发现抑制TRPV1能增加破骨样巨噬细胞比例，加重腹主动脉瘤的进展，其机制可能通过CaMKII-AMPK/NLRP3炎症小体新通路来实现。因此，申请者创新性地选取巨噬细胞破骨样转化作为切入点，拟搜集腹主动脉瘤临床组织标本、体内利用骨髓移植构建巨噬细胞相对特异性敲除TRPV1的小鼠腹主动脉瘤模型、体外提取小鼠骨髓单核巨噬细胞，通过缺失/恢复、RNA干扰等手段，探讨TRPV1通过CaMKII-AMPK/NLRP3通路介导巨噬细胞破骨化在腹主动脉瘤中的作用机制。本课题的完成将为腹主动脉瘤的临床药物治疗提供新的理论依据及治疗靶点。

Inflammation is a key factor in the development of abdominal aortic aneurysms, in which the phenotypic transformation of macrophages plays an important role. Recent studies have found that osteoclast-like transformation of macrophages is related to the progression of abdominal aortic aneurysms, but its regulatory mechanism and functional changes remain unclear.TRPV1, as an important Ca2+ channel protein, could regulate the formation of osteoclasts in bone tissue. Our previous experiments have found that inhibition of TRPV1 could increase the proportion of osteoclast-like macrophages and aggravate the progression of abdominal aortic aneurysm in mice. The mechanism may be realized through the new CaMKII-AMPK/NLRP3 inflammasome pathway. Thus, the applicant innovatively selected osteoclast-like transformation of macrophages as a new breakthrough,and planned to collect human tissue samples of abdominal aortic aneurysm, construct mouse abdominal aortic aneurysm model with relatively macrophage-specific knockout of TRPV1 by bone marrow transplants in vivo and extract mouse bone marrow mononuclear macrophages in vitro. Then we will reveal the mechanism of TRPV1 regulating osteoclast-like transformation of macrophages in abdominal aortic aneurysm through CaMKII-AMPK/NLRP3 inflammasome pathway using missing/recovery, RNA interference and other methods. The present investigation will provide new theoretical basis and therapeutic target for abdominal aortic aneurysm.