Relb组建的Il9超增强子在Th9分化和哮喘中的作用及应用研究

Th9细胞在寄生虫免疫、自身免疫性疾病及抗肿瘤中都发挥重要作用。但是，其分化机制目前还了解甚少。以往的研究主要集中在Il9基因的启动子区，虽然报道了多个相关转录因子，但都不能很好解释Th9的分化机制。超增强子是2013年新提出的概念，我们这里首次将超增强子引入到Th9分化机制中，并用实验证实了Th9的成功大量分化需要在Il9基因区形成一个超增强子（Il9 super-enhancer，IL9SE）。超增强子的核心功能区IL9SEa在诱导Th9分化中发挥关键作用。Relb是Il9超增强子形成的关键分子。超增强子抑制剂能抑制体内哮喘的发生。因此，我们提出Th9分化的新模型即超增强子/启动子双调控模型，并将进一步深入研究IL9SE的功能、形成机制及在动物模型中评价Il9超增强子在哮喘中的治疗价值。本课题的成功开展，不仅能从本质上阐明Th9的分化机制，而且能为哮喘的临床治疗提供全新的靶点。

T helper 9 (Th9), a newly identified Th subset, plays critical roles in host-protective responses to parasitic worms and allergic airway diseases. However, the differentiation process and transcriptional regulation of its signature cytokine Il9 are still poorly understood. Here, we found that Th9 differentiation needs a super-enhancer at Il9 locus (we called Il9 super-enhancer, IL9SE). IL9SE is required for Th9 differentiation and its core element (IL9SEa) interacts with Il9 promoter to induce Th9 differentiation. Moreover, Relb acts as a pioneer factor to establish IL9SE and is required for Th9 differentiation. Most importantly, inhibition of IL9SE formation in vivo prohibits Th9 differentiation and asthma development. Thus, we hypothesize that Th9 differentiation is cooperatively regulated by IL9SE and Il9 promoter. Herein, my specific aims are: (1) To further determine the function of IL9SE in Th9 differentiation; (2) To study how IL9SEa functionally interacts with Il9 promoter to drive Il9 expression; (3) To further determine the role of Relb in the establishment of IL9SE; (4) To investigate how Relb establishes IL9SE; (5) To further study the role of IL9SE in Th9 differentiation and asthma development in vivo. This proposed study will not only establish a new model for the differentiation of Th9 but also provide a proof-of-principle new target for asthma treatment.