M2型巨噬细胞在修复脑缺血损伤过程中扮演重要角色，但调控其极化的机制尚不明确。前期工作初步发现神经营养因子MANF影响M2型巨噬细胞极化，改善脑缺血损伤；进一步研究发现MANF显著下调脑组织M2型巨噬细胞中转录抑制子DREAM蛋白水平并升高A20表达量，但对DREAM mRNA水平无影响。基于前期工作提出科研假说：MANF通过诱导DREAM蛋白降解、上调A20表达、抑制NF-κB p65入核，调控M2型巨噬细胞极化进而减轻脑缺血损伤。为论证该科研假说，本课题拟应用MANF-/-小鼠及基因沉默、免疫共沉淀等技术：①从正反两方面明确MANF调控脑缺血后M2型巨噬细胞极化；②揭示MANF调控的M2型巨噬细胞极化对脑缺血损伤的保护作用；③阐明MANF通过促进DREAM蛋白降解、上调A20表达、抑制NF-κB p65入核，进而调控M2型巨噬细胞极化。本课题可为治疗缺血性脑卒中药物的开发提供新靶点。

M2 macrophage can alleviate cerebral ischemia injury, therefore it is meaningful to develop the target that modulates M2 macrophage polarization. Our team found that neurotrophic factor MANF affects M2 macrophage polarization, decreases infarct size and lowers mortality rate after stroke. MANF has no effect on DREAM mRNA level, but down-regulates DREAM expression. Based on the previous study, we proposed the hypothesis: MANF induces DREAM degradation, increases A20 expression, suppresses NF-κB p65 translocation, which modulates M2 macrophage polarization and protects ischemia injury. In order to verify this hypothesis, MANF-/- mice, gene silencing, gene over-expression, immunofluorescence, co-immunoprecipitation are applied to prove: ①MANF modulates M2 polarization after cerebral ischemia, ②M2 modulated by MANF protects brain from ischemia injury, ③MANF induces DREAM degradation, up-regulates A20 expression, inhibits NF-κB p65 translocation and modulates M2 macrophage polarization. Our study will provide new sight for ischemic stroke therapy.