免疫相关GTP酶（IGRM/Irgm1）在多发性硬化症发病过程中对巨噬细胞型别转换的影响及相关机制研究

多发性硬化(MS)是中枢神经系统慢性炎性疾病。大量研究集中在T细胞对MS发生和转归的影响，而作为T细胞活化和发挥效应的必要条件-单核/巨噬细胞（M?）在MS中的作用并没给予足够重视。最新的研究及我们的前期工作表明：M?可分为不同型别，不同M?亚型在MS及其动物模型EAE的发病机制中扮演着不同的角色；同时发现IRGM/Irgm1是调节M?功能的重要因子；Irgm1基因敲除小鼠EAE发病明显低于野生型小鼠。结合前期工作和现有M?型别转换的知识，本项目以小鼠EAE模型和MS病人外周血样本为研究对象，从全新的角度探讨不同类型M?对疾病不同阶段的影响及相关机制。通过本项目我们将解决：1、不同型别M?在MS/EAE病程中扮演什么角色？2、不同型别M?如何反馈性调控效应性T细胞？3、IRGM/Irgm1通过何种机制调控M?型别转化？这些问题的解决将为MS临床治疗提供重要的理论依据和全新的思路。

Multiple sclerosis (MS) is a chronic inflammatory disease of central nerve system. Studies mainly focus on the effect of T cells on the occurrence and result of MS, however macrophage (M?), as the necessary condition of the activation and playing effect of T cells, has not been emphasized enoughly. Latest research and our previous work showed that M? could differentiate into different subtypes, and different subtypes could play different role during the pathology of MS and its animal model-EAE. At the same time we found that IRGM/Irgm1 is the important factor for the regulation of M?. The severity of EAE based on Irgm1 knock out mouse is obviously lower than WT EAE mice. Combining our previous work and nowadays knowledge about the switch of M?, our project employ mice EAE model and blood sample of MS patients as study objects, explore from a completely new view the effect of different subtype of M? on the different stage of disease and the relative mechanism. We will resolve through the project: 1, What character does different subtype of M? play in the pathology of MS/EAE? 2, How does the subtype of M? feedback on the effective T cells? 3, What kind of mechanism does IRGM/Irgm1 play in the regulation of the switch of M?? The resolution of the above questions would provide important theoretical basis and entirely new idea for the therapy of MS.