TSP4减少巨噬细胞迁移抑制腹主动脉瘤发生的机制研究

腹主动脉瘤（AAA）瘤壁中巨噬细胞浸润是AAA重要始动因素，如何抑制AAA巨噬细胞浸润是血管领域重要科学问题，但其机制尚未完全阐明。我们前期研究发现凝血酶敏感蛋白4（TSP4）敲除小鼠诱导的AAA明显增大，瘤壁巨噬细胞浸润增加。进一步研究发现，TSP4可抑制巨噬细胞FAK磷酸化，灭活RhoA；结构预测提示TSP4可与整合素β3结合。因此申请人推测TSP4可能通过与整合素β3结合抑制FAK磷酸化，灭活RhoA进而减少巨噬细胞迁移，抑制AAA形成。本课题将在前期工作基础上，以巨噬细胞灶性粘着斑为研究切入点，聚焦整合素β3/FAK/RhoA通路，采用人体标本、体内外实验，多角度多模型分析：TSP4对AAA发生的作用，深入研究TSP4抑制AAA中巨噬细胞浸润的机制，筛选并评价小分子多肽对抑制AAA形成的作用。本项目将从新的角度阐明AAA发病机制，为AAA防治提供新的理论依据及干预靶点。

Macrophage infiltration in the wall of abdominal aortic aneurysm (AAA) is one of the important initiating factors of AAA. How to inhibit macrophage infiltration in AAA is an important issue in vascular diseases, but its mechanism has not been fully elucidated. Our previous study found that TSP4 (Thrombospondin-4) knockout mice could be induced a significant increase in AAA size and macrophage infiltration. Further studies revealed that TSP4 inhibits macrophage FAK phosphorylation and inactivates RhoA. Protein structure prediction suggests that TSP4 binds to integrin β3. Therefore, we hypothesize that TSP4 may inhibit FAK phosphorylation and inactivate RhoA by binding to integrin β3 resulting in macrophage migration decrease and AAA suppression. Based on previous work, this project will focus on macrophage focal adhesion and integrin β3/FAK/RhoA pathway. With human specimens, in vitro and in vivo experiments, multi-angle and multi-model, we plan to analyze the role of TSP4 in inhibiting macrophage infiltration in AAA, screening and evaluating the role of small peptides in inhibiting AAA formation. This project will clarify the pathogenesis of AAA from a new perspective and provide a new theoretical basis and intervention target for AAA prevention and treatment.