靶向EED调控巨噬细胞功能治疗多发性硬化症的分子机制研究

多发性硬化症（MS）是一种炎性介导的中枢神经系统脱髓鞘疾病，严重可致终身瘫痪。现有药物仅可延缓疾病进展，且存在严重不良反应，故亟需寻找MS治疗新策略。近年来，参与MS炎症的巨噬细胞因具有免疫激活和抑制的双重功能成为MS治疗的关键靶细胞，对其调控机制和干预策略开展深入研究可推动MS治疗。前期研究发现，组蛋白修饰蛋白EED抑制剂可显著促进巨噬细胞M2极化，巨噬细胞敲除Eed或回输EED抑制的巨噬细胞均能有效改善EAE（MS动物模型）症状，该作用可能与H3K27me3介导的IRF4转录激活相关。基于此，本课题将进一步明确EED在巨噬细胞M2型极化及MS中的关键作用，阐明阻断EED抑制H3K27me3激活IRF4转录调控巨噬细胞M2型极化治疗MS的分子机制。本课题不仅将揭示EED在巨噬细胞及MS中的全新生物学功能，还将阐明巨噬细胞调控MS的全新机制，为设计与发现调控巨噬细胞治疗MS策略提供新思路。

Multiple sclerosis (MS) is a demyelinating disease caused by inflammation, which can lead to lifelong paralysis. The clinical medication can only delay the disease progression accompanied by serious adverse reactions. Therefore, it is urgent to find new treatment strategies for MS. Due to the dual functions of immune activation and suppression, macrophages have been found to be a key target for MS therapy in recent years. Further studies on the regulation mechanisms and intervention strategies towards macrophages can effectively promote MS therapy discovery. Our previous study found that the inhibitors of histone modifying enzyme EED significantly promoted M2 polarization of macrophages. Besides, Eed deficiency in macrophages or transferring EED-inhibited macrophages efficiently alleviated symptoms of EAE mice (an animal model of MS), which may be related to H3K27me3 mediated activation of transcription factor IRF4. Based on this, our study will further clarify the key role of EED in MS, and illustrate the molecular mechanisms of EED-regulated IRF4 signal in M2 polarization of macrophages to treat MS. We will not only reveal the new biological functions but also the mechanisms of EED in macrophages and MS, thus providing novel ideas for designing and discovering novel strategies targeting macrophage for MS.