TET2调控Foxp3 DNA去甲基化在变应性鼻炎中的作用及机制研究

变应性鼻炎（allergic rhinitis，AR）发病率持续增高，表观遗传调控在其中的作用备受关注。本项目组既往研究显示Foxp3高甲基化是导致AR中Treg细胞功能下降的重要因素，但具体机制不明。新近报道TET家族参与Foxp3DNA主动去甲基化过程，同时我们发现AR小鼠Treg细胞TET2表达显著降低，且与Foxp3高甲基化相关，据此推测TET2可能通过调控Treg细胞Foxp3去甲基化而在AR免疫平衡调节中发挥关键作用。本课题拟应用Tet2-/-小鼠构建AR模型，通过过继免疫和质粒转染等技术，运用FACS、oxBS-Seq及PICh等方法，检测TET2表达、Foxp3去甲基化状态及变应性炎症改变，从临床、动物和细胞水平探讨TET2调控Foxp3去甲基化在AR发病机制中的作用，并深入研究其调控机制，为通过表观遗传学手段恢复Treg细胞功能从而治疗AR提供理论依据。

The incidence of allergic rhinitis (AR) has been increasing in recent decades, which could be attributed to the epigenetic modifications. Our previous study has showed that hypermethylation of Foxp3 was the key factor resulting in the down-regulated Treg in AR, but the mechanism was unclear. Recent articles manifested that TET was involved in the active demethylation of Foxp3 DNA. Our preliminary work revealed that the decrease of TET2 mRNA expression in Treg cells of AR mice was associated with the hypermethylation of Foxp3 DNA. So it is reasonable to speculate that TET2 may be a regulator of Foxp3 DNA demethylation and has a key role in the immune disorder of AR. Our research plans to investigate the role and mechanism of TET2-mediated Foxp3 DNA demethylation in AR, by constructing AR model using Tet2-/-mice, with the methods of plasmids transfection, adoptive transfer immunization, and the techniques of FACS, oxBS-Seq and IPCh to detect expression of TET2, demethylation of Foxp3 DNA, and change of allergic inflammation. This study would enhance the understanding of epigenetic mechanism in AR and provide tractable target for therapeutic intervention.