miR-124靶向iASPP在缺血性脑损伤小胶质细胞极化表型中的作用及机制研究

①Polarized phenotypes of microglia (M1 phenotype shows neurotoxic property and M2 phenotype shows neuroprotective property) play a critical role in inflammation, immunity and nerve regeneration after stroke. miR-124, as a new target of inflammation, is an important marker of microglia polarized phenotypes and a new study suggested that iASPP may be involved in the neurogenic inflammation, but the role and mechanism of both of them in microglial polarized phenotype have not been reported till now. ②Our previous study found that miR-124 regulated iASPP by targeting its 3'UTR; in the M1 phenotype, miR-124 expression decreased and the expression of iASPP increased; and vice versa in the M2 phenotype, which suggested that miR-124 targeting iASPP may play an important role in different microglial polarized phenotypes. ③In this study, RNA interference, miRNA transfection, lentivirus infection, middle cerebral artery occlusion, et al., will be used in this project. We will confirm the role of miR-124 targeting iASPP on different microglial polarized phenotypes in cerebral ischemia; to reveal the pathway regulate the function of microglia polarization on the survival of neurons and oligodendrocytes, myelination and the release of inflammatory factor. This project will provide new ideas, new ways and new targets for the treatment with cerebral ischemia by inducing transformation of microglial polarized phenotypes.

①小胶质细胞的极化表型（神经毒性的M1型和神经营养保护的M2型）在中风后炎症反应、免疫调节及神经再生中起着至关重要的作用。炎症调控新靶点miR-124是小胶质细胞极化表型的重要标志，最新研究提示iASPP可能参与神经炎症反应，但两者在小胶质细胞极化表型中的作用机制尚未见报道。②我们前期研究发现miR-124可以靶向调控iASPP；在M1表型中，miR-124表达降低，iASPP表达升高；在M2表型中则反之，提示miR-124靶向iASPP可能在小胶质细胞不同极化表型中发挥重要作用。③本研究基于体内和体外缺血模型，采用激光捕获、甲基化PCR、原位杂交、病毒感染等技术，验证脑缺血中miR-124靶向iASPP在小胶质细胞不同极化表型中的作用，揭示此通路通过调节小胶质细胞极化对神经元和少突胶质细胞存活、髓鞘形成及炎症进程中的作用。此项目将为M2表型小胶质细胞治疗脑缺血提供新思路、新途径和新靶标。

小胶质细胞的极化表型（神经毒性的M1型和神经营养保护的M2型）在中风后炎症反应、免疫调节及神经再生中起着至关重要的作用。炎症调控新靶点miR-124是小胶质细胞极化表型的重要标志。研究基于体内和体外缺血模型，验证脑缺血中miR-124和iASPP在小胶质细胞不同极化表型中的作用。研究结果显示miR-124在M2小胶质细胞中表达亦增加，并且miR-124的表达促进小胶质细胞向M2型细胞的转化。iASPP在M2型中表达显著上调，并可能在少突胶质祖细胞分化中发挥重要作用。尽管我们研究发现miR-124可以靶向调控iASPP；但是在小胶质细胞中，两者没有呈现很好的调控关系，提示在小胶质细胞中，iASPP的表达可能是多途径调控作用的结果。项目揭示在缺血性脑损伤中，miR-124和iASPP在小胶质细胞极化中的作用及对神经元存活和少突胶质细胞分化中的作用。此项目将为M2表型小胶质细胞治疗脑缺血提供新思路、新途径和新靶标。