锚定蛋白Gab1调控树突状细胞介导气道过敏性炎症的机制研究

Docking protein Gab1 is essentially involved phosphorylation, serving important roles in regulation of various cell physiological functions. Recent clinical genetic work strongly suggests a causative role of human gab1 gene as one of susceptibility genes of asthma. However it remains much unclear about in vivo roles of docking protein Gab1 in regulation of lung injuries and inflammatory responses. Germline knockout of Gab1 in mice causes embryonic lethality. In this study, Cre-loxP system was thus utilized to generate tissue specific Gab1 knockout in monocytes/macrophages using Lysm-Cre promoter (Lysm-Cre/Gab1flox/flox). We found loss of Gab1 attenuates OVA-induced airway injury and inflammation, suggesting a potential role of Gab1 in dendrite cell-induced asthmatic responses. Dendritic cells (DCs) are the most important antigen-presenting cells in the lungs, and are also receiving emerging attention into the central role of Gab1 in allergic asthma. Based on these, we plan to generate the Gab1-deficient DC transgenic mice using CD11c-Cre promoter to further unveil Gab1-regulated DC cell functions in lung asthmatic injury. We believe our studies help us better understanding into etiology of asthma, and also provide a potential new avenue for this untreatable disease.

锚定蛋白Gab1介导磷酸化信号，参与多种细胞生理学功能调控。最近有遗传学研究提示人类gab1基因可能是过敏性哮喘主要易感因素之一，然而Gab1在肺损伤炎症功能缺乏了解。Gab1敲除小鼠(Gab1 KO)胚胎致死，我们预实验构建髓系单核细胞Gab1条件性敲除小鼠(LysM-Cre/Gab1flox/flox)研究Gab1调控机制。初步结果显示Gab1缺失显著缓解卵清蛋白介导的气道炎症，髓系来源细胞回输实验进一步提示Gab1可能在髓样树突状细胞(DC)调控方面具有重要意义。DC介导抗原加工与提呈是过敏性哮喘炎症的关键进程。本课题在此基础上，构建DC细胞条件性敲除Gab1小鼠(CD11c-Cre/Gab1flox/flox)，深入研究Gab1调控DC介导过敏性气道炎症的生理学意义，明确Gab1参与DC成熟以及抗原递呈的作用方式。相信预期成果有助于理解过敏性炎症发病机制，有望为临床诊治提供新思路。

哮喘是一种常见的慢性气道炎症性疾病，由遗传因素和环境因素(如过敏原，呼吸道病毒感染等)共同参与调控的，目前为止并无可以治愈哮喘的药物。Gab1在哺乳动物体内广泛表达，介导细胞的增殖、凋亡、迁移、极化等多种重要的生理过程。近年来一项大规模的遗传学研究发现gab1是哮喘的一个新的易感基因，然而其在哮喘及过敏性炎症中的功能及其调控机制尚未报道。我们的研究结果显示Gab1在树突状细胞中的缺失可以缓解尘螨（HDM）诱导的过敏性哮喘的发生，进一步的细胞功能研究显示Gab1的缺失对DC的成熟，对抗原的吞噬以及抗原递呈过程均没有影响，而是阻断了CCL19介导的DC向淋巴结的迁移过程。机制的研究显示Gab1通过介导P115RhoGEF与Rho的结合调节Rho的活化，正向调控了DC的迁移过程，该研究可以帮助更好地理解DC在过敏性哮喘的病理过程，并为该疾病的诊断治疗提供新的潜在靶点。