miR-155负向调控免疫应答的机制及其在哮喘发病中的作用

项目名称： miR-155负向调控免疫应答的机制及其在哮喘发病中的作用

项目编号： No.30871134

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 轻工业、手工业

项目作者： 修清玉

作者单位： 中国人民解放军第二军医大学

项目金额： 32万元

中文摘要： 哮喘发病的核心机制是Th1/Th2细胞因子失衡，但其确切机理尚未明确。最新研究表明，微小RNA家族成员miR-155的缺失可导致小鼠出现与哮喘患者类似的Th1/Th2细胞因子失衡和气道重构，但机制不明。我们通过双报告基因荧光素酶活性检测实验及体外基因操作实验证明了细胞毒T淋巴细胞相关抗原-4（CTLA-4）、B、T淋巴细胞弱化因子（BTLA）均是miR-155在CD4+T细胞活化过程中的重要靶点；CTLA-4、c-maf、BTLA能够共同介导miR-155的负向免疫调控作用机制；此部分研究丰富了miR-155通过靶向作用于共刺激分子调控T细胞活化的理论，阐明了miR-155调控T淋巴细胞因子的机制；鉴于现有研究已说明CTLA-4和气道重构关系密切，miR-155可能通过CTLA-4参与患者气道重塑。通过观察哮喘患者miR-155、CTLA-4的表达状况，初步阐明了miR-155与哮喘发病的相关关系及其参与哮喘发病的机制；可能为治疗哮喘提供新思路。通过哮喘患者血清PBMC标本中microRNA差异表达的筛查，为探讨其它的microRNA在转录后水平参与免疫调控从而参与哮喘发病打下了基础。

中文关键词： 哮喘；miR-155；CTLA-4；BTLA；T细胞活化

英文摘要： The core mechanism of asthma is the disequilibrium of Th1/Th2 cytokines, but the exact mechanism of it is still unknown. Recent researches showed that deletion of miR-155, a new member of miro-RNA family, can induce asthma-like symptoms and signs such as disequilibrium of Th1/Th2 cytokines and airway remodeling in mice, but the mechanism of which was also unknown.We showed that both CTLA-4 and BTLA were targets of miR-155 during na?ve CD4+T cell activation through using the Dual-luciferase reporter assays and gene manipulation in vitro. Since both of them could inhibit CD4+T cell activation, our results indicated that miR-155 may enhance CD4+T activation through inhibiting both the expression of CTLA-4 and BTLA. On the basis of CTLA-4 was involved into the pathogenesis of airway remodeling, miR-155 may be involved in the process of asthmatic patients through targeting CTLA-4. We found the expression of miR-155 decreased while the expression of sCTLA-4 increased in asthmatic patients, which elucidated miR-155 may be involved in asthma through targeting sCTLA-4,this may provide new method for the therapy of asthma.We also observed different expression level of different microRNA in asthmatic patients compared with healthy controls through microRNA array,and found other microRNAs may be involved in the pathogenesis of asthma, which may be benefit for investigating the possible roles of other microRNAs in the pathogenesis of asthma.

英文关键词： Asthma; MiR-155; CTLA-4; BTLA; Tcell Activation