白三烯受体在多发性硬化症中的作用及机制研究

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.

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。

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，受体药物干预能改善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。为此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。. 在本项目的支持下，我们深入研究了包括白三烯在内的几个主要GPCR受体在多发性硬化中的功能及机制，取得了一系列的主要进展，包括发现白三烯受体cysLT1调控T细胞迁移促进致病性细胞进入中枢神经系统、以及白三烯受体BLT1在调节DC细胞因子分泌中的重要功能；揭示了腺苷受体A2B在树突细胞(DC)白介素6分泌过程中的调控作用；发现抗癫痫药物丙戊酸钠（VPA）能调节T细胞免疫平衡及有效减轻小鼠疾病症状，提示VPA在治疗MS中的潜在价值；发现阿片受体KOR在髓鞘恢复以及EAE发病过程中的重要作用；筛选发现治疗疱疹病毒的药物BVDU具有抑制DC细胞分泌IL6，并且具有治疗EAE小鼠的价值；发现嘌呤受体P2Y12通过调节Th17分化，并参与EAE的病理过程；发现GPCR信号转导分子Gaq在多发性硬化发生中起着重要的调控作用。综上，我们系统阐述了GPCR在治疗多发性硬化中的作用及机制，为疾病治疗提供了许多潜在的治疗靶点。在权威期刊上发表包括Nature communications在内的SCI论文7篇，申报专利4项，相关成果详细情况参见成果在线。