髓鞘相关糖蛋白MAG通过NgR1抑制精神分裂症海马少突胶质前体细胞分化的作用机制研究

少突胶质前体细胞（OPC）分化障碍与精神分裂症发生发展及认知功能障碍密切相关。髓鞘相关糖蛋白MAG与NgR1结合可抑制轴突的生长、促进施万细胞凋亡，而OPC膜亦存在NgR1，但其作用尚不清楚。我们发现脱髓鞘区域OPC数量明显增多，推测MAG与OPC膜上NgR1结合可能具有抑制OPC分化成熟的作用。鉴于此，本项目拟利用精神分裂症动物模型和体外培养OPC，研究髓鞘碎片/MAG对OPC分化、增殖及凋亡的作用；进而通过脑立体定位注射、细胞干预等方法降低MAG和NgR1活性，明确二者对脱髓鞘小鼠海马OPC分化的影响；利用条件性NgR1敲除和体外NgR1质粒转染技术，探讨MAG对精神分裂症海马OPC的调控作用，明确NgR1下游P75蛋白裂解及其抑制OPCs分化成熟的分子机制，为阐明脱髓鞘疾病认知功能障碍及海马进行性脱髓鞘的发病机理提供新的理论依据，并为临床治疗或缓解精神分裂症等脱髓鞘疾病提供新的靶点。

Oligodendrocyte dysfunction and demyelination is closely related to the occurrence and development of schizophrenia and cognitive dysfunction. The binding of myelin-associated glycoprotein (MAG) and NgR1 can inhibit the growth of axon and promote the apoptosis of Schwann cells. NgR1 also exists in the membrane of oligodendrocyte precursor cells (OPCs), but its effect is still not clear. We found that the number of OPCs in demyelinating area increased significantly in schizophrenia mice. It is speculated that the binding of MAG and NgR1 on OPCs membrane may inhibit the differentiation and maturation of OPCs. Therefore, this project plans to use schizophrenia animal model and OPCs culture in vitro to study the effects of myelin fragments / MAG on OPCs differentiation, proliferation and apoptosis. Furthermore, the activities of MAG and NgR1 will be decreased by stereotactic injection and cell intervention, and the effects of them on the differentiation of OPCs in the hippocampus of demyelinating mice will be clarified. Using conditional NgR1 knockout and in vitro NgR1 plasmid transfection technology, the regulatory effect of MAG on OPCs in schizophrenic hippocampus will be studied, and molecular mechanisms of the cleavage of p75 protein, a downstream protein of NgR1, and its inhibition of OPCs differentiation and maturation will be investigated, which will provide a new theoretical basis for clarifying the cognitive dysfunction of demyelinating diseases and the pathogenesis of progressive demyelination of hippocampus, and provide new targets for clinical treatment or alleviation of schizophrenia and other demyelination diseases.