结核分枝杆菌ESAT-6蛋白对巨噬细胞NADPH氧化酶活性的调控作用及其分子机制研究

项目名称： 结核分枝杆菌ESAT-6蛋白对巨噬细胞NADPH氧化酶活性的调控作用及其分子机制研究

项目编号： No.81471562

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： 戴亚蕾

作者单位： 同济大学

项目金额： 65万元

中文摘要： 结核病是一种由结核杆菌感染引起的传染性疾病。巨噬细胞作为一种重要免疫细胞，在抗结核感染中起着重要作用。我们前期研究发现结核分泌蛋白ESAT-6诱导ROS产生是通过与巨噬细胞表面TLR2结合而发挥作用，NADPH氧化酶活化是ESAT-6刺激巨噬细胞导致ROS产生、JNK/p38和NF-kB活化及细胞因子MCP-l等分泌的关键。但ESAT-6通过哪些信号途径活化NADPH氧化酶尚不清楚。为此我们利用高通量检测平台，对ESAT-6诱导巨噬细胞活化样本进行检测，并筛选出12个具有显著变化的相关信号转导分子和6个直接参与mROS产生的分子，提示ESAT-6在不同程度上多方面调控ROS产生。本课题将从分子、细胞和动物模型等不同层次探讨EAST-6诱导巨噬细胞NADPH氧化酶活化途径及相关分子之间相互作用机制，明确ESAT-6在结核感染过程中对巨噬细胞的调节作用。为药物研发提供新的分子靶标和干预策略。

中文关键词： 结核分枝杆菌；ESAT-6；巨噬细胞；活性氧；NADPH氧化酶

英文摘要： Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis infection. Macrophage is an important immune cell which plays critical role during this process. Our previous studies demonstrated that mycobacterium tuberculosis ESAT-6 induced ROS generation via TLR2 on the surface of macrophage. Activation of NADPH oxidase is a key factor for ESAT-6 stimulates macrophage producing ROS, activating JNK/p38 and NF-kB, secreting cytokine such as MCP-1 etc. However, it is unclear which signaling pathways are involved during ESAT-6 inducing NADPH oxidase activation. Thus, we used high throughput method screening high expression molecules after ESAT-6 induced macrophage activation, and have found there are 12 molecules related with signaling transduction and 6 molecules related with mROS generation. These results indicated that ESAT-6 may play multiple roles in regulating ROS generation. This project will investigate 1) how ESAT-6 inducing NADPH oxidase activation and its possible signaling pathway and/or molecular mechanisms by using cell line and animal models; 2) clarify ESAT-6 regulating role in macrophage activation during Mycobacterium tuberculosis infection. These findings will provide new insight for the development of drug target of Mycobacterium tuberculosis and intervention strategies of treating tuberculosis.

英文关键词： Mycobacterium tuberculosis;ESAT-6;Macrophage;ROS;NADPH oxidase