iTreg的表观调控及其在自身免疫性疾病中的作用机制

项目名称： iTreg的表观调控及其在自身免疫性疾病中的作用机制

项目编号： No.31330026

项目类型： 重点项目

立项/批准年度： 2014

项目学科： 免疫学

项目作者： 王宏林

作者单位： 上海交通大学

项目金额： 303万元

中文摘要： 调节性T细胞（Treg）分为nTreg和iTreg。iTreg产生于胸腺之外，需要TCR信号、TGF和IL-2。与nTreg相比，iTreg较稳定，不易向Th1、Th17和Tfh细胞转变，对治疗慢性疾病的疗效更好。尽管过去对iTreg研究较多，但microRNA介导的表观调控机制至今未见报道。课题组前期研究发现：miR-31在iTreg分化前后相差100倍以上。课题组首次完成了miR-31过表达和miR-31条件性基因剔除小鼠的构建。预实验发现miR-31过表达导致iTreg的分化被显著抑制，同时促进自身免疫性疾病发生。该项目拟进一步求证：1）miR-31靶基因；2）miR-31对iTreg细胞及疾病的作用机制；3）miR-31转录的信号网络；4）靶向miR-31诱导iTreg分化用于转化医学研究。这些问题的阐明有利于增强对iTreg表观调控的理解，为自身免疫性疾病的诊治提供新思路新方法。

中文关键词： 表观调控;调节性T细胞;FoxP3;小分子RNA;自身免疫性疾病

英文摘要： Forkhead box P3 (FoxP3)+ CD4+ regulatory T (Treg)-cells can be divided into natural Treg (nTreg)-cells and adaptive Treg (iTreg)-cells. iTreg-cells are generated outside the thymus, and require TCR signaling and the cytokines TGF-beta1 and IL-2. In contrast to nTreg-cells, iTreg-cells are more effective in controlling established inflammatory diseases, and more resistant to the conversion to T helper (Th)1-, Th17-, and follicular helper T (Tfh)-cells under inflammatory conditions. Despite the mechanisms of iTreg-cell generation have been intensively focused in the past, our understanding of molecular mechanisms, particularly microRNA (miRNA)-mediated epigenetic regulation involved in the iTreg-cell generation is lacking. Our prliminary data we showed that microRNA-31 (miR-31), a small non-coding RNA, decreased over 100 folds in TGF-beta1-induced iTreg-cells compared to controls. We created miR-31 overexpression transgenic and miR-31flox/flox/CD4-Cre conditional knockout mice. We found that miR-31 overexpression inhibited iTreg-cell induction, and facilitated autoimmunity. This project intends to carry out further investigations: 1) the target gene(s) of miR-31; 2) the contribution and mechanism of conditional knock-out of miR-31 in development and differentiation of iTreg-cells, and in the development of autoimmunity; 3) the transcription signaling pathway(s) regulating miR-31; 4) The utility of targeting miR-31 in translational research. The clarification of these issues may be conducive to enhancing our understanding of the apparent regulatory networks of Treg-cells, and may lead to create novel ideas and strategies for both diagnosis and treatment of autoimmune disorders.

英文关键词： Epigenetic Regulation;Regulatory T Cells;FoxP3;MicroRNA(s);Autoimmune Disease