细胞膜表面粘附分子Mxra8：新型溶瘤病毒M1的受体研究

本课题组首次鉴定了新型溶瘤病毒M1，并研究了其重要的药理学与生物学特征[1-10]。然而，M1病毒的受体（M1R）作为介导M1进入肿瘤细胞的核心关键分子，一直未被阐明。本项目预实验通过生物信息学分析和基因功能注释发现，肿瘤细胞对M1病毒的敏感性和细胞表面的粘附信号通路密切相关；进一步的研究确定了细胞膜表面分子Mxra8为候选的M1R；利用siRNA干扰和慢病毒过表达，发现Mxra8显著促进M1病毒的感染和抗肿瘤效应。申请者拟进一步采用冷冻电镜等方法确证Mxra8与M1病毒的直接相互作用并描述其结构特征；检测肿瘤细胞M1R的丰度和细胞对M1病毒敏感性之间的相关性，确立M1R作为M1病毒临床治疗的分子标志物；利用M1R模型筛选小分子阻断剂，为M1病毒临床应用的风险控制提供方法。本项目通过阐明溶瘤病毒M1药效学的关键分子，为溶瘤病毒M1临床应用的精准诊断和治疗提供坚实的科学依据。

Our team firstly identified oncolytic M1 virus and illustrated its important phamaceutical and biological proporties[1-10]. However, the receptor of M1 virus (M1R) as the most important molecule, has not yet been found. Bioinformatics and gene function analysis indicates that cell adhension signaling pathway contributes to the sensitivity of cancer cells to M1 virus and Mxra8 as an candidate M1R. SiRNA and over-exprssion of Mxra8 prove that Mxra8 significantly promotes the infection and anti-tumor efficacy of M1 virus. The applicant furtherly plan to use electron cryomicroscopy and other assays to confirm that Mxra8 and M1 virus are dirctly interacted and figure out the structure foundation, to build the relationship between the expression of Mxra8 in cancer cell and the effect of M1 virus to cancer cells, so as to establish Mxra8 as biomarker of M1 virus therapy, to construct M1R model and screen small molecule blocker of M1 virus to supply candidate assay to control the risk of M1 virus therapy. By identifying the key molecule of M1 virus, our project will provide solid scientific base for M1 virus accuracy diagnosis and theray in the clinic.