缺血性脑卒中是严重危害人类生命健康的常见疾病。近年来研究表明，缺血性脑卒中后活化的小胶质细胞可极化为不同的表型发挥不同的作用，脑梗死后抑制小胶质细胞M1型极化、促进M2a型极化可有效减轻组织损伤，促进神经功能恢复，但其机制尚不明确。我们前期研究发现脑缺血后排斥性导向分子a (RGMa)在神经元、星形胶质细胞、血管内皮细胞中表达升高，调控轴突再生、胶质瘢痕形成及血管再生。然而，RGMa在小胶质细胞中的作用尚不清楚。本项目拟从体外细胞和在体小鼠两个层面上，通过慢病毒等方式干预RGMa、neogenin、ALK6、PPAR-γ、NF-κB p65表达，采用过继性转移方法治疗，应用多种分子生物学技术，明确RGMa对缺血性脑卒中后小胶质细胞极化的调控作用及机制，阐明小胶质细胞极化对神经元和少突胶质细胞的损伤死亡及再生的作用及机制，探索治疗时间窗，为缺血性脑卒中治疗提供新靶点和实验依据。

Ischemic stroke is one of the leading causes of death and disability worldwide. Recent studies identify that the activated microglia polarizes toward distinct phenotypes to play different roles in ischemic injury. Inhibition of microglial M1 polarization and facilitation of M2a polarization would reduce tissue injury and promote functional recovery after stroke. However, the underlying mechanisms of it are unclear. Our previous studies found that the expression of repulsive guidance molecule a (RGMa) is up-regulated in neurons, astrocytes and epithelial cells. The up-regulated RGMa is involved in multiple pathological events of stroke, including axon regeneration, glial scar formation, and angiogenesis. But the role of RGMa on microglia is still unknown. Therefore, we plan to elucidate the role and the underlying mechanisms of RGMa in the regulation of microglial polarization after ischemic stroke. We would also explore the function and mechanisms of microglial polarization on death and regeneration of neurons and oligodendrocytes in ischemic injury and the therapeutic time window for modulation of microglial polarization after stroke. To clarify them, we would establish a mice middle cerebral artery occlusion/reperfusion model in vivo and culture brain cells in vitro, apply lentivirus (LV) and specific inhibitors to regulate the expression of RGMa, neogenin, ALK6, PPAR-γ, and NF-κB p65, perform LV infection, stereotactic surgery and adoptive transfer, and use a lot of molecular biology methods. This project will provide a new therapeutic target and experimental basis for ischemic stroke treatment.