脱髓鞘性损伤是多种神经系统疾病共有的病理特征，少突胶质前体细胞(OPCs)成熟是髓鞘再生的治疗靶点。我们前期研究发现脱髓鞘病灶区的OPCs不能正常分化，髓鞘调节因子MYRF的表达显著下调，但其调控机制未知。由于小胶质细胞来源的miR-615可靶向调节MYRF，我们提出 “小胶质细胞激活→miR-615表达→细胞外囊泡递送miR-615→MYRF表达沉默→OPCs分化受阻”的作用机制假说。本课题拟采用荧光素酶报告基因法和RNA免疫沉淀技术，解析MYRF 3’-UTR与miR-615的结合位点；进而通过细胞共培养、器官型脑片培养体系测试炎症微环境下小胶质细胞调控OPCs分化的作用方式；最后利用靶向拮抗miR-615的AAV评估其对多种脱髓鞘动物模型的治疗作用。该研究有助于阐明小胶质细胞与OPCs之间信息通讯的机制，可为炎症微环境中细胞的命运决定与分化研究提出新思路，为脱髓鞘疾病治疗提供新靶点。

Demyelinating disease is a common pathological feature of various neurological diseases. Maturation of oligodendrocyte precursor cells (OPCs) is a therapeutic target for remyelination. Recently，we found that the OPCs in the demyelinated lesions could not be differentiated normally, and the expression of the myelin regulatory factor MYRF was significantly down-regulated, but its regulatory mechanism was unknown. Since microglia-derived miR-615 can target MYRF, we propose a underlying mechanism of "microglia activation → mi615 expression → extracellular vesicle delivery miR-615 → MYRF expression silencing → OPCs differentiation blocked". This study intends to use the luciferase reporter gene assay and RNA immunoprecipitation technology to analyze the binding site of MYRF 3'-UTR and miR-615. Based on the cell co-culture and organotypic slice culture, we will investigate the mechanism of activated microglia effect on OPCs differentiation. Finally, the AAV vector which targeting to antagonizing miR-615 were used for test the therapeutic effect on multiple demyelinating animal models. This study will elucidate the mechanism of the cell communication between microglia and OPCs, and provide a new therapeutic target on demyelinating diseases.