MiR-23b在EAE模型中促进髓鞘再生的作用机制研究

Multipe sclerosis (MS) is a major demyelinating disease of the central nervous system (CNS) with varied and unpredictable symptoms that leads to disability. Experimental autoimmune encephalomyelitis (EAE) is the most commonly used experimental model for MS. We found that intracerebroventricular administration of LV-miR-23b, a negative regulator of inflammatory response, significantly improved functional recovery in EAE. Concomitantly, elevation of miR-23b levels significantly increased newly generated myelinating oligodendrocytes in the CNS of EAE mice. Moreover, administration of miR-23b shifted polarization of M1 to M2 microglia/marcrophages. Our in vitro experiments demonstrated that elevation of miR-23b promoted OPCs to differentiation into myelinating oligodendrocytes. Based on our prelimanary data, we hypothesize that elevation of miR-23b has potential as a therapy for MS/EAE by promoting OPC differentiation into myelinating oligodendrocytes. To test this hypothesis, we will test the therapeutic effect of LV-miR-23b in the chronic stage of EAE. We will also test the M1-inhibiting and M2-promoting effect of miR-23b on microglia/marcrophages. Furthermore, we will test the direct effect of miR-23b on myelination/remyelination and oligodendrocyte/neuron protection in vitro and in vivo. This project, if successful, will provide findings confirming potential of miR-23b as a novel therapy for MS and will elucidate the mechanisms underlying its action.

多发硬化（MS）是以中枢神经系统慢性炎症脱髓鞘病变为特征的自身免疫性疾病。EAE是目前研究MS的理想动物模型。我们发现miR-23b的表达能够明显缓解病变引起的脱髓鞘；miR-23b参与调控小胶质细胞和巨噬细胞由促炎表型向抗炎表型的转换；miR-23b显著促进少突胶质前体细胞的分化，提示其促进髓鞘再生、逆转炎症反应造成的神经功能性损伤的全新作用。基于此，本课题拟通过慢病毒介导miR-23b表达系统观察其对EAE病程发展慢性阶段的影响；通过体内体外实验明确miR-23b参与小胶质细胞/巨噬细胞由促炎表型向抗炎表型转化，进而间接促进髓鞘再生的分子功能；利用喂食Cuprizone小鼠模型阐明miR-23b直接参与少突胶质前体细胞向成熟的少突胶质细胞分化的作用，通过探讨其作用的信号通路及靶分子，阐明其促进髓鞘再生的作用机制，为中枢神经系统变性疾病（如多发硬化症）的治疗提供有效的治疗靶点和分子药物。

多发硬化（MS）是以中枢神经系统慢性炎症脱髓鞘病变为特征的自身免疫性疾病。EAE是目前研究MS的理想动物模型。我们发现过表达miR-23b能够明显缓解疾病的发生发展；机制上，miR-23b通过靶向结合趋化因子CCL7 3’-UTR从而抑制了炎性细胞浸润到CNS从而缓解了疾病的发生发展；另外，我们发现miR-23b也能够通过调节小胶质细胞表型M1/M2的转变，间接地促进髓鞘再生；最终，我们还利用体外细胞培养，脑片离体培养以及cuprizone脱髓鞘模型证明了miR-23b对OPCs的直接促分化作用。该项目的完成，对揭示miR-23b在自免疫疾病及炎性脱髓鞘疾病的内在机制具有重要意义。为miR-23b在炎性细胞迁移及髓鞘再生功能研究方面提供了新的理论依据。