miR-146a通过调控中枢内源性IFN-β参与实验性自身免疫性脑脊髓炎病程发生发展的机制研究

Multiple sclerosis (MS) disease, one of the central nervous system (CNS) inflammatory demyelinating diseases is the major reason to cause CNS disability in young adults. IFN-β has been used as the first-line disease-modifying drug for MS for therapy for many years. Although it was thought that IFN-β would work more effectively in CNS, how CNS-restricted IFN-β involved in the physiopathogenesis of MS remain unknown. Previously we found that miR-146a was significantly up-regulated in the brain and spinal cord of EAE (experimental autoimmune encephalomyelitis, a mouse model of MS) mice, in line with the significantly decreased expression of IFN-β in CNS tissues. As miR-146a play a key role in regulating the type 1 interferon system, we hypothesized that CNS restricted miR-146a may involve in EAE pathogenesis through regulating CNS in-situ IFN-β secretion. In this project, we will use real-time PCR and FISH methods to furtherly characterize the spatiotemporal and cell-specific expression of miR-146a in EAE mice. Then from the molecular and cellular level to uncover the role of CNS restricted IFN-β in development of EAE in both in vitro and in vivo experiments plus using IFNAR deficient mouse. In addition, we will try to identify how miR-146a regulate the expression of IFN-β in the CNS of EAE mice. This project will help us to better understand the physiopathogenesis of MS/EAE.

多发硬化（MS）是造成青壮年神经系统功能性残障的重要因素，IFN-β作为其临床一线用药使用广泛。尽管认为中枢IFN-β可能具有更好的治疗效果，但中枢特异性IFN-β如何参与MS的病程尚不清楚。我们前期发现miR-146a在MS动物模型实验性自身反应性脑脊髓炎（EAE）小鼠脑和脊髓中表达显著上调，而IFN-β的表达显著下降。基于miR-146a在调控1型干扰素系统方面的重要作用，我们推测EAE中，miR-146a可能通过调控中枢内源性IFN-β参与EAE疾病的发生发展。因此，本研究拟用实时定量PCR，荧光原位杂交等技术深入分析miR-146a在EAE中的时空和细胞差异表达特征，结合体内体外手段以及IFNAR基因敲除小鼠，从分子和细胞水平证实中枢内源性IFN-β参与EAE病程的作用机制，并明确miR-146a调控IFN-β表达的作用机理。研究结果对进一步阐明MS/EAE的病程机制具有重要意义。