磷酸-鞘氨醇通过作用于G蛋白偶联的细胞外受体可以介导多种生物学效应，它由鞘氨醇在鞘氨醇激酶的催化下生成，而两种鞘氨醇激酶在中枢神经系统中皆呈高表达。我们在前期工作中发现调控鞘氨醇信号可以阻断中枢神经系统炎症下的血管内皮细胞激活和免疫细胞招募。在本项目中，我们将使用活体显微镜和抗体芯片，探索鞘氨醇信号在中枢神经系统及免疫细胞招募中的角色，并回答以下问题：1.鞘氨醇信号在中枢神经系统炎症中如何发挥作用？2. 为什么调控鞘氨醇受体信号可以有效地抑制血管内皮的激活？3.鞘氨醇激酶和鞘氨醇受体信号在中枢神经系统炎症下的生理病理学意义是什么？我们的研究将为通过靶向鞘氨醇信号调控中枢神经系统炎症提供思路和理论线索。

Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that acts extracellularly via G protein-coupled receptors to regulate many physiological processes. S1P is formed by phosphorylation of the membrane lipid sphingosine, as catalyzed by sphingosine kinases, which are highly expressed in CNS. Our preliminary data showed that targeting S1P signal significantly blocked endothelial activation and subsequent leukocyte recruitment in CNS inflammation. Using protein array and intravital microscopy, a cutting edge technique, we will explore the roles of sphingosine signaling in mediating immune cell recruitment into the CNS and answer the following scientific questions: 1. How does sphingosine signal get involved in CNS inflammation and leukocyte recruitment cascade? 2. How does targeting S1P receptors affects phosphorylation of many transcriptional signals, therefore interfere subsequent endothelial activation and expression of adhesion molecules. 3. The roles for sphingosine kinase and S1P receptors in CNS inflammation will be systemically examined. Our research will provide evidence and a useful strategy for treating CNS inflammatory diseases with leukocyte infiltration via targeting sphingosine-1-phophate signaling pathways.