新型趋化因子PSMP在单核细胞的动员与募集和腹主动脉瘤的发生与发展中的作用

Abdominal aortic aneurysm (AAA) is a highly lethal vascular disease and the related mechanism is still not fully understood. Monocyte motility and recruitment play a critical role in vascular inflammation. PC3-secreted microprotein (PSMP) is a novel chemokine, and CCR2 has been identified as its receptor. The role of PSMP in vascular disease is still elusive. We established PSMP-/- mice and found that PSMP deficiency inhibited elastase-induced AAA as well as monocyte motility in bone marrow and monocyte recruitment in aortic wall. Moreover, purified PSMP induced bone marrow-derived monocyte migration and peripheral blood-derived monocyte transmigration in vitro. Thus, we hypothesized that PSMP promotes monocyte motility and recruitment and aggravates AAA formation. Firstly, we plan to explore the effect of PSMP in AAA through neutralizing antibody and PSMP-/- mice in three AAA models. Secondly, we will explore PSMP-modulated monocyte motility in bone marrow and monocyte recruitment in vascular tissues both in vitro and in vivo. Thirdly, we are going to identify the downstream signaling pathways of CCR2 mediated PSMP-induced monocyte motility and recruitment by using specific inhibitors and gene knockout mice. Through this project, we expect to explore novel mechanism of AAA formation.

腹主动脉瘤是一类具有高死亡风险的血管疾病，其发病机制还不完全清楚。单核细胞的动员与募集参与了血管炎症病理过程。PSMP是一种新发现的趋化因子，CCR2为其作用的受体，而PSMP在血管疾病的发生发展过程中的作用尚无报道。我们构建了PSMP敲除的小鼠，发现PSMP缺陷可抑制弹力酶诱导的腹主动脉瘤的发生并减少单核细胞的骨髓动员和主动脉壁募集，并且纯化的PSMP可诱导单核细胞的趋化和跨内皮迁移。因此，我们假设：PSMP可促进单核细胞的动员与募集并加重腹主动脉瘤的发生与发展。我们将利用不同腹主动脉瘤模型及PSMP中和抗体与基因敲除小鼠明确PSMP对腹主动脉瘤的影响；通过细胞和动物实验检测PSMP对单核细胞骨髓动员和血管局部募集的调控作用；利用抑制剂或基因敲除动物明确与PSMP致病作用相关的CCR2下游信号，为腹主动脉瘤的发病机制注入新的内容。

单核细胞向血管壁募集，进而分化为巨噬细胞，并通过极化参与腹主动脉瘤的发生与发展。我们发现新型趋化因子PSMP通过CCR2趋化单核细胞，并且PSMP缺陷显著抑制腹主动脉瘤的形成和饮食诱导的肥胖，提示PSMP可能是防治腹主动脉瘤和肥胖的潜在靶点。同时，我们关注巨噬细胞极化的调控机制，发现甲基化酶Mettl3介导的RNA m6A甲基化介导了巨噬细胞M1型极化，相关机制为M1型关键转录因子Stat1的mRNA发生m6A甲基化，导致RNA稳定性增加，进而促进M1型巨噬细胞极化。此外，我们还发现基质蛋白COMP是一种内源性AT1-beta-arrestin-2的信号偏向拮抗剂，可抑制腹主动脉瘤的发生与发展。本项目共发表带标注SCI论文5篇，IF>5的4篇，申请国内专利1项。