RECK通过Wnt7通路调控少突胶质前体细胞分化影响EAE发病的作用机制研究

多发性硬化（MS）是中枢神经系统内的一种炎症性脱髓鞘疾病，影响全球约230万人。脱髓鞘的轴突难以有效复髓鞘是MS治疗的主要障碍，而复髓鞘的瓶颈是少突胶质前体细胞(OPCs)不能分化为成熟少突胶质细胞（OLs）。到目前为止，还没有一种促进髓鞘再生的疗法被批准，因此本课题聚焦OPC分化过程。我们在前期研究中通过基因芯片从EAE模型/对照组中筛选出具有显著表达差异的RECK基因。通过CRISPR技术和条件性敲除小鼠分别在体内/体外水平验证了RECK缺失对OPC分化的抑制，并进一步发现其敲除影响Wnt7信号通路。结合文献报道，我们提出假说：RECK竞争性结合Wnt7，阻断Wnt7/Fz5/Lrp5/6信号通路对OPC分化的抑制。本课题拟在前期工作基础上，进一步探究RECK促进OPC分化和髓鞘再生的分子机制，验证其分子治疗潜力，为进一步阐明MS病理过程、寻找治疗新靶点提供理论依据和实验基础。

Multiple sclerosis (MS) is an inflammatory demyelinating disease in the central nervous system, which affects about 2.3 million people worldwide. The main obstacle of MS treatment is that demyelinated axons are difficult to be remyelinated effectively, and the bottleneck of remyelination is that oligodendrocyte precursor cells (OPCs) can not differentiate into mature oligodendrocytes (OLs). So far, no drug has been clinically approved to promote remyelination. So this project focuses on the process of OPC differentiation. In our previous study, we screened RECK gene with significant expression difference from EAE model/control group by microarray. CRISPR technique and conditional knockout mice were used to verify that RECK deletion inhibited OPC differentiation in vitro and in vivo. Furtherly, we found that RECK knockout affected Wnt7 signaling pathway during OPC differentiation. Based on previous reports and our preliminary findings, we hypothesized that RECK competitively binds to Wnt7 and blocks the inhibition of OPC differentiation by Wnt7/ Fz5/Lrp5/6 pathway. In this project, we will further explore the molecular mechanism of RECK promoting OPC differentiation and remyelination, verify its molecular therapeutic potential, and provide theoretical and experimental basis for further elucidating the pathological process of MS and looking for new therapeutic targets.