脑缺血后，促炎作用的M1型小胶质细胞占优势，介导炎症、加重脑损伤。发现关键的调控因子特异性减少M1型并促进其向神经保护作用的M2型转化，是当前国际上亟待解决的问题。我们基于前期研究提出假说：转录因子/核受体Nur77是缺血性卒中后小胶质细胞表型和功能分化的关键调控分子。本课题将采用Nur77条件敲除和过表达小鼠、相应小胶质细胞，制备体内外脑缺血模型，利用流式，免疫化学，分子和生化、神经行为学等技术和方法：1）阐明Nur77促进卒中后M1型小胶质细胞向M2型转化的作用和机制；2）揭示Nur77调控的小胶质细胞在缺血性脑损伤和修复中的作用；3）靶向Nur77的机制，筛选治疗缺血性卒中的药物，并提供研发调控小胶质细胞功能的新药的药物筛选模型。研究结果为发现卒中后小胶质细胞表型、功能转化的关键调控因子及其作用机制提供新的和更深的认识，并为寻找靶向炎性小胶质细胞调控机制提供创新和有效的策略。

After cerebral ischemia, the pro - inflammatory M1 – like microglia are the dominant phenotype, which play a detrimental role that aggregates ischemic brain injury and limits neuro-repair. To identify the key regulatory factors, which control the microglia polarization, and transformation switch between M1 like and M2 like microglia are timely and clinically significant. Based on the published literature and our pilot studies, we hypothesize that a transcription factor/nuclear receptor Nur77 is the key regulator, functions in reducing M1-like microglia, but promoting M2-like microglia polarization, and as well as the switching of M1/M2 phenotypes and beneficial functional differentiation of the activated microglia after ischemic stroke. To test our hypotheses, in this project we plan to use Nur77 conditional knockout mice, Nur77 overexpression mice, and primary microglia or isolated microglia from brain ischemia model in vivo, using flow cytometry sorting, immunohistochemistry and immunocytochemistry, molecular and biochemical, histopathological, neural behavior and other techniques and methods: 1) elucidate the effects and mechanisms of Nur77 in modulating M1-like microgliapolarization, and switching M1/M2 transformation after ischemic stroke; 2) reveals the role of Nur77 in regulating microglia-mediated brain injury and repair; 3) development of target to the Nur77 targeting based therapy strategy and compound screening platform for treating ischemic stroke. If successful, these proposed experiments should provide insight of how Nur77 modulate microglia-mediated brain damage and repair, which might ultimately yield a novel and effective ischemic stroke therapy development.