最大细胞表面受体家族、十次诺贝尔奖对象、全球最大的药靶，这些标签表明了G蛋白偶联受体（GPCR）在人类健康中的重要性及研究热度。前人及我们的报道提示GPCR在多发性硬化症（MS）中同样重要，而系统深入的研究仍然缺乏。我们平行精确检测365个受体在MS模型小鼠（EAE）中的时空表达谱，发现白三烯受体成员之一上调近百倍位列首位，另三个也有显著变化，受体药物干预能显著抑制EAE发病，与前人及我们的报道一致。此前的研究以药物干预为主要手段，细胞机制有待阐明，而利用全身敲除结合条件敲除的方法研究基因功能逐渐成为目前公认的金标准。本项目拟首先研究全身敲除白三烯受体对EAE的影响；其次从DC功能、T细胞分化/迁移/趋化、星形/少突/小胶质细胞功能等MS主要相关细胞逐一探索受体作用的细胞机制；最后用相应条件敲除小鼠结合EAE建模明确受体功能及机制。为MS及其它自身免疫病的诊治提供基于GPCR的新靶点。

G-protein coupled receptor (GPCR) is one of the most important and hottest research fields in human health. And as the largest receptor family, GPCR has been conferred Nobel Prize for ten times, and occupied the first place in global drug targets. Previous studies including ours indicated that GPCR also has important roles in Multiple Sclerosis (MS), one of the autoimmune diseases, while the systemic and intensive study of GPCR in MS pathogenesis was kept to be performed. Here by analyzing the spatial and temporal expression profile of 365 GPCRs in EAE, the mouse model of MS, we found that one member of the leukotriene receptor is up-regulated for 100 folds during EAE and occupied the first place in all the analyzed GPCRs, the other three leukotriene receptors all changed significantly. We also demonstrated they play important roles in EAE pathogenesis by agonists or antagonists manipulation of the leukotriene in EAE model. The above observation kept accordance with the others and our own published results. However, those reported studies mainly focused in the drug manipulation, and the underlying cell mechanisms were largely kept unknown, and nowadays the genetic manipulation such as gene knockout and conditional knockout become golden standard for gene function study. So here we proposed to study the function and mechanism of leukotriene receptors in MS pathogenesis in three main sides: Firstly, we will study receptor function in EAE pathogenesis by gene knockout, then we will intensively explore the underlying cell mechanisms by analyzing the main MS related cells event such as dendritic cell function, T cell differentiation/migration/chemotaxis and microglia/astrocyte/ oligodendrocyte function, finally we will use the conditional knockout mouse to further verify the function and cell mechanism of leukotriene receptors in EAE pathogenesis. This study will reveal GPCR as new diagnostic markers and therapeutic targets for MS and other autoimmune diseases.