miR-223-gp130-PI3K信号通路在登革病毒感染中作用及其机制的研究

项目名称： miR-223-gp130-PI3K信号通路在登革病毒感染中作用及其机制的研究

项目编号： No.81471957

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 安静

作者单位： 首都医科大学

项目金额： 90万元

中文摘要： 登革出血热和登革休克综合征是登革热（DF）患者死亡的主要原因，其临床特点为血管通透性增加引起的出血和休克，但发生机制不明。新近研究中我们发现：登革病毒（DV）感染下调miR-223的表达。软件预测发现IL-6st（编码gp130）为miR-223的靶基因之一，且gp130能够激活PI3K，后者可通过调控small G Rac1-微丝途径，引起内皮细胞收缩、血管通透性增加。为此本项目拟研究：① 证明IL-6st为miR-223的靶基因之一；② miR-223通过gp130调控PI3K-Rac1-微丝的活性，进而参与DV的感染和致病过程; ③利用动物实验，给予miR-223激动剂和拮抗剂，探讨miR-223作为抗病毒药物靶点的可能性; ④ 证明DV非结构蛋白（NS）5通过miR-223启动子区甲基化，使miR-223下调表达。期望本研究为深入阐明DV的感染机制及防治DV感染提供全新的思路。

中文关键词： 登革病毒；微小RNA；gp130；Rac1；miR-223

英文摘要： Dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS)is the major cause of death in patients with dengue fever (DF). Bleeding caused by increased vascular permeability is the main clinical features of dengue fever. The activation of Rac1- microfilament cytoskeleton pathway not only can promote dengue virus (DV) infection, but also cause vascular endothelial cells (VEC) contraction and permeability increase. However, the mechanism underlying that DV infection activate Rac1- microfilament cytoskeleton pathway is unclear. In recent research, we found that DV infection induced down-expression of miR-223, and is closely related to the activation of Rac1-microfilament pathway. Further bioinformatics analysis indicated that the IL-6st (encoding gp130), a target gene of miR-223, may activate PI3K, and then regulate Rac1 - microfilament signaling pathways, and in turn cause change of VEC shape. Therefore this study will perform the following experiments: (1) Identifying that IL-6st is one of the target genes of miR-223; (2) the The role and mechanism of miR-223 in DV infection，mainly focusing on whether the miR-223 regulates the activation of PI3K-Rac1-microfilament via gp130; (3) Using mouse model and agomir-223 and antagomir-223，the possibility will be explored whether miR-223 act as antiviral drug target; (4) Mechanism of down-expression of miR-223 induced by DV infection: methylation in promoter of miR-223 and role of NS5 in the process. This study will provide new insight into further clarifying the mechanism of DV-host interaction and prevention of DV infection.

英文关键词： Dengue virus;miRNA;gp130;Rac1;miR-223