RGS19对嗜酸细胞性食管炎FcεRI信号传导通路的影响及其作用机制的研究

A number of clinical and laboratory research evidences suggests that IgE –mediated allergy plays an important role in eosinophilic gastrointestinal disorders(EGID) especially eosinophilic esophagitis(EoE) development, but the exact mechanism is not clear. FcεRI is a key molecule in the physiological mechanisms of allergy, and it has high affinity for IgE. Moreover, eosinophilic esophagitis elevated the gene expression level of FcεRI. IgE may be combined with FcεRI and regulates its expression level, leading to changes of the downstream signaling pathways, such as Ras and Src signaling, finally trigger the eosinophilic inflammation of the gastrointestinal tract. Previously, we identified that RGS19 inhibits oncogenic Ras (RasGV) or Src (SrcYF) induced neoplastic transformation and Raf/ERK signaling. This study focus on the detection of the following things: 1) FcεRI mRNA and protein expression, the binding relationship of IgE and FcεRI on esophageal smooth muscle cells (ESMC); ①establish EoE mice model, investigate FcεRI mRNA & protein expression, and the binding relationship of IgE and FcεRI; ②verify the effects of IgE on severity of EoE, Ras signaling and expression of RGS19, explore the role of FcεRI in EoE and its possible singnal transduction passways; ③compare the differences of EoE severity, downstream signaling and expression of RGS19 between overexpression and knock out of RGS19 in transgenic mice, find out the possible role of RGS19 on FcεRI induced eosinophilic esophagitis pathogenesis. The completion of this project will help further understanding of the pathogenesis of EoE and provide a theoretical basis for EoE clinics and new therapeutic directions.

多项临床及实验室研究证据表明，IgE介导的变态反应在嗜酸细胞性食管炎（EoE）的发生发展中发挥着重要的作用，但具体机制尚不明确。FcεRI是变态反应进程的关键分子，与IgE有很高的亲和性，同时EoE中FcεRI基因表达水平升高。IgE可能经由与FcεRI相结合及对其表达水平、下游Ras&Src信号传导的调节触发EoE炎症反应的发生。我们以往的研究证实，RGS19对Ras的成瘤转换及信号传导均有抑制作用。本研究拟通过①建立EoE小鼠模型，验证EoE中FcεRI表达情况及IgE与FcεRI的关系；②通过检测拮抗IgE后，EoE炎症程度及信号传导的变化，探讨FcεRI在EoE中的作用并探寻可能的信号传导途径；③经由过表达及敲除RGS19，测定EoE炎症程度炎症程度及信号传导的变化，探讨RGS19在FcεRI介导的EoE机制中的作用及机制。本项目的完成有助于为EoE的诊疗指出新的潜在治疗方向。