本实验室发现CRF家族肽Urocortin (UCN)促进血管炎症，Ucn抗体可逆转之，但其下游机制远未清楚。S1P-S1PR1，2在血管炎症的中的作用一直存争议，S1PR3作用不明。PLA2的促炎作用得到公认，其中cPLA2与Lp-PLA2作为血管炎症的重要标志得到重视。我们新近的研究发现，CRFR1激动可上调cPLA2从而引起内皮细胞表达ICAM-1，并诱导血管平滑肌细胞迁移，该作用可被S1PR3阻断剂CAY10444消除。提示UCN可能通过S1P-S1PR3-PLA2参与炎症。本项目拟用S1PR1,2,3沉默的内皮细胞，探索UCN通过S1P-S1PRs-PLA2参与血管炎症的作用及可能下游机制--Rho-ROCK-NF-κB/P38/PPARγ-samd3信号通路；采用巨噬细胞-内皮黏附及S1PR3-/-& CRFR1-/-小鼠等效应实验分析UCN与S1PR3-PLA2的关联作用。

Previously, we found that Urocortin (UCN) played a proinflammatory role in the development of vasculitis, which could be abolished by Anti-UCN. The effects of S1P-S1PR1,2 in vasculitis have been controversial. Both of their proinflammatory and inhibitory functions were reported. S1PR3's role in vasculitis remains unclear. PLA2 has been identified as proinflammatory factors in the process of vasculitis, of which cPLA2 and LP-PLA2 were recognized as important markers for vasculitis. Our recent data showed that UCN regulated PLA2 expression and hence ICAM-1 expression in vascular endothelial cells. Moreover, UCN upregulated cPLA2 and hence induced cell migration in vascular smmoth muscle cells, which could be abolished by S1PR3 antagonist, CAY10444. These results suggest that UCN may participate in vasculitis via S1P-S1PR3-PLA2. This project aims to elucidate the mechanisms of UCN participating in vasculitis via S1P-S1PR3-PLA2. And the detailed signaling pathways involved will be investigated, including Rho-ROCK-NF-κB,P38,and PPARγ-samd3 pathways. S1PR1,2,3 silenced endothelial cells and monocytes will be used. Moreover, the macrophage-endothelium monolayer adhesive experiment will be performed. In vivo experiments will be carried out in S1PR3-/-、CRFR1-/- mice for analysis of links among UCN and S1P-S1PR3-PLA2.