条件性敲除p38α激酶对Th细胞分化和变应性炎症的调控作用

It has been reported that the p38 signalling pathway in different cell types plays different roles in the pathogenesis of allergic disease. CD4 Th cells are critical regulator of allergic disease. So our study will focus on the regulation and mechanism of p38 MAPK on CD4 Th cell differentiation and HDM-induced allergic airway inflammation using a p38α conditional deletion mouse strain, which deletes p38α only in CD4 Th cells. Our previous study has confirmed the phenotype that deletion of p38α in CD4 Th cells promotes the Th2 differentiation, decreases the Th1 and Th17 differentiation and also increases the recruitment of eosinophils and neutrophils in the lung of HDM-induced airway inflammation mice. Then we try to find the intrinsic and extrinsic mechanism of p38α mediating this process. First, we’ll detect the expression of cytokine receptors on the surface of CD4 Th cells upstream of p38α. Then we’ll detect the expression of transcription factors and kinases downstream of p38α. At last, we’ll use RNA interference technology, blocking antibody or related inhibitor to determine the main mechanism. Our study is expected to be beneficial for the clinical therapies of allergic disease .

p38激酶是变应性炎症的重要调控因素，其对变应性炎症的调控具有细胞特异性。由于CD4 Th细胞是变应性炎症的主要效应细胞，本课题将首次应用CD4 Th细胞条件性敲除p38α基因小鼠，在HDM诱导的变应性气道炎症模型中研究p38α信号通路对CD4 Th细胞分化及变应性疾病的调控作用及机制。本研究的前期研究结果证实在HDM诱导的变应性气道炎症模型中，抑制CD4 Th细胞中p38α信号通路能够促进Th2细胞的分化，阻碍Th1和Th17细胞的分化；并且促进了小鼠肺部炎性细胞的浸润。接下来，我们将通过检测p38α上游CD4 Th细胞表面相应细胞因子受体的表达以及下游细胞分化相关转录因子及激酶的变化，找到p38α调节CD4 Th细胞分化的分子机制，并通过使用药物抑制剂、封闭抗体或RNA干扰等技术对相应机制进行体内、体外试验验证。本研究期望为变应性疾病的治疗寻找新的作用靶点。

哮喘等变应性疾病通常被认为主要是由Th2细胞介导的嗜酸性粒细胞性慢性炎症。有关调控Th2分化的因素还鲜有报道。本课题主要围绕在变应性疾病中调控Th2细胞分化的内在及外在因素进行了研究。本项目首先研究了CD4+T细胞内在的p38α信号通路对CD4+T细胞分化及其介导的变应性哮喘的调控作用。因树突状细胞在调控CD4+T细胞分化中发挥着重要作用，基于此我们研究了树突状细胞中的p38α信号通路及Fas信号通路对变应性疾病及其中CD4+T细胞分化的调控作用及机制。我们的研究发现：1）阻断CD4+T 细胞中p38α信号通路，能明显加重小鼠的变应性哮喘反应，并且促进Th2细胞的分化。2）DCs中p38α信号通路能够抑制Th2细胞的分化并降低Th2细胞介导的变应性哮喘的严重程度。3）Fas敲除的BMDCs能够促进HDM诱导的受体小鼠肺部炎性反应，并通过 Fas-ERK-IL-12信号通路促进Th2细胞的分化。本课题的研究内容将为以p38α/Fas为靶点治疗Th2细胞依赖性的变应性疾病提供理论依据。