Dock2 在宿主抗鼠类柠檬酸杆菌感染中的作用机制研究

炎症性肠病（IBD）是常见肠道疾病，其病理机制非常复杂，包括遗传缺陷、免疫功能紊乱和肠道菌群失调等。细胞分裂贡献者2 (Dock2) 是一种鸟嘌呤交换因子，已知Dock2在各种免疫细胞迁移和活化中有重要作用，且发现肠道疾病患者有Dock2 突变， 但Dock2在体内的结肠炎及细菌感染中的作用未见报道。预实验显示：Dock2-/-小鼠对鼠类柠檬酸杆菌导致的肠炎有很强的易感性；与适应性免疫缺陷的Rag1-/-小鼠比较，该小鼠不仅存在适应性免疫缺陷，也有先天性免疫缺陷；后者缺陷与固有淋巴细胞无关而可能与巨噬细胞有关；该小鼠肠道菌群也存在失调。为明确Dock2调节宿主对结肠炎易感性的作用机制，本项目拟研究Dock2控制巨噬细胞迁移及其杀菌机制，并通过肠道菌群转移和抗生素处理实验来探讨Dock2对维持正常肠道菌群的重要性。本研究将为理解IBD的复杂病理机制和可能的治疗方案提供科学依据。

The pathogenesis of inflammatory bowel disease (IBD), a common digestive disease, is very complicated and is involved with factors including genetic defect, disorders of the host immune function, and imbalance of gut microbiota. Dedicator of cytokinesis 2 (Dock2) is a guanine nucleotide exchange factor. Although it is known that Dock2 plays an important role in the migration and activation of different immune cells and Dock2 mutation has been identified in patients with digestive diseases, the in vivo role of Dock2 in colitis and bacterial infection has not been reported. Our preliminary data shows Dock2-/- mice are highly susceptible to Citrobacter rodentium infection-induced colitis. In comparison to Rag1-/- mice that completely lose adaptive immunity, Dock2-/- mice has a defect in innate immunity, as well as in adaptive immunity. The defect in innate immunity is not due to defect in innate lymphoid cells(ILC), but is associated with the dysregulation of macrophage function. In addition, Dock2-/- mice also have imbalanced gut microbiota. In this study, we will investigate how Dock2 regulates migration and bactericidal function of macrophages and the importance of Dock2 in maintaining normal gut microbiota through fecal transplantation and antibiotic treatment experiments. This study will not only shed light on the understanding of the mechanisms of IBD, but also provide rationale for potential therapeutic interference of this disease.