GCN2在Th9细胞发育分化及过敏性哮喘中的作用和调控机制研究

Allergic asthma is a kind of chronic immune disease. For the complexity of its pathogenesis, there is no drug could treat it effectively. In recent years, it has been found that Th9 cells and their secreted IL-9 play important roles in allergic asthma. GCN2 plays an important role in a variety of immune cells and autoimmune diseases, but little is known about the differentiation of CD4+ helper T cells. Our recent experimental results showed that GCN2 specifically regulated Th9 cell differentiation and Th9 cell-related allergic asthma. Therefore, we propose a scientific hypothesis that GCN2 plays a role in allergic asthma by directly regulating Th9 cell development. Based on this scientific hypothesis, this study mainly investigated the effects of GCN2 on Th9 cell differentiation and the molecular mechanism; The effects of GCN2 on allergic asthma and whether GCN2 plays a role in allergic asthma by directly regulating Th9 cell differentiation. The completion of this project will systematically clarify the influence and regulatory mechanism of GCN2 on Th9 cell differentiation and allergic asthma, and provide theoretical basis for GCN2 to become a potential therapeutic target for allergic asthma and GCN2 inhibitor to become a potential therapeutic drug for allergic asthma.

过敏性哮喘是一种慢性免疫性疾病。由于其发病机制的复杂性，目前还没有药物能够根治它。近年来研究发现，Th9细胞及其分泌的IL-9在过敏性哮喘中发挥重要作用。GCN2在多种免疫细胞和自身免疫性疾病中发挥重要作用，而其对CD4+辅助性T细胞发育分化的影响还知之甚少。我们近期研究发现GCN2相对特异的调控Th9细胞分化及与Th9细胞相关的过敏性哮喘。因此，我们提出科学假设：GCN2通过直接调控Th9细胞发育分化进而在过敏性哮喘中发挥作用。本课题主要基于此科学假设系统的研究GCN2对Th9细胞发育分化的影响及分子机制；GCN2对过敏性哮喘的影响，以及GCN2是否是通过直接调控Th9细胞发育分化进而在过敏性哮喘中发挥作用。本课题的完成将系统的阐明GCN2对Th9细胞发育分化和过敏性哮喘的影响及调控机制，为GCN2成为潜在的过敏性哮喘治疗靶点及GCN2抑制剂成为潜在的治疗过敏性哮喘的药物提供理论依据。

过敏性哮喘是一种慢性免疫性疾病。由于其发病机制的复杂性，目前还没有药物能够根治它。近年来研究发现，Th9细胞及其分泌的IL-9在过敏性哮喘中发挥重要作用。GCN2在多种免疫细胞和自身免疫性疾病中发挥重要作用，而其对CD4+辅助性T细胞发育分化的影响还知之甚少。本课题主要围绕GCN2对于Th9细胞发育分化及与其密切相关的过敏性哮喘的作用和调控机制展开，系统地研究了GCN2对Th9细胞发育分化的影响及其调控Th9细胞发育分化的分子机制；GCN2对过敏性哮喘的影响，以及GCN2是否是通过直接调控Th9细胞发育分化进而在过敏性哮喘中发挥作用。研究结果主要发现：1、GCN2能够相对特异地促进Th9细胞在体外和体内的发育分化；2、GCN2在过敏性哮喘中发挥正向调控作用，并且其主要通过直接调控Th9细胞发育分化进而在过敏性哮喘中发挥作用；3、GCN2通过HIF1α依赖的糖酵解通路促进Th9细胞的发育分化。本课题系统地阐明了GCN2对Th9细胞发育分化和过敏性哮喘的影响及调控机制，为GCN2成为潜在的过敏性哮喘治疗靶点及GCN2抑制剂成为潜在的治疗过敏性哮喘的药物提供理论依据。