Host innate immune-microbial interactions and intestinal inflammation

描述（由申请人提供）：宿主先天免疫系统和肠道微生物群之间的相互作用是特发性人类炎症性肠病（IBD）发病机制中的近端事件。解决IBD的发病机制并最终治愈和预防这些慢性衰弱疾病取决于使用实验模型和人体系统来更好地理解先天免疫和肠道微生物之间的功能相互作用，这些相互作用决定了粘膜组织中效应T细胞亚群与调节性T细胞亚群的分化和激活。我们假设共生菌群的亚群优先激活保护性和破坏性先天信号通路，这些信号通路综合激活粘膜先天和抗原提呈细胞分泌细胞因子，促进调节性和效应性T细胞反应。这些相互作用的细菌激活的先天和适应性途径介导稳态和效应免疫反应，并可用于治疗目的。这一假设将通过六个完全整合的研究人员的协同努力来解决，他们在先天免疫和宿主-微生物群相互作用方面具有互补的专业知识，并由两个高度利用的核心提供便利。项目1 (Jenny Ting)：“肠道炎症中的nod样受体”。项目2 (Balfour Sartor)：“IL-10在APC调节对共生菌的保护性和致病性T细胞反应中的作用”。项目3 (Scott Plevy)：“肠道炎症中肠道微生物群对巨噬细胞IL-10和IL-12的调节”。项目四（约翰·罗尔斯）：“微生物对全身中性粒细胞功能的调节”。项目负责人将得到两个高度互动的核心的支持，这两个核心已经促进了合作研究。核心A：生物和转基因啮齿动物和斑马鱼核心(核心联合董事，博士。萨特和罗尔斯)。核心B：人体组织和基因组学核心(联合董事，博士；Scott Plevy， Hans Herfarth和Shehzad Sheikh)。在Cores的协助下，研究人员正准备加速了解先天免疫系统如何在健康和疾病中与肠道微生物群相互作用。这一知识可能对IBD和许多由先天免疫与肠道微生物群相互作用失调引起的疾病产生重大的公共卫生影响。

DESCRIPTION (provided by applicant): Interactions between the host innate immune system and the enteric microbiota are proximal events in the pathogenesis of the idiopathic human inflammatory bowel diseases (IBD). Solving the pathogenesis of IBD and ultimately curing and preventing these chronic, debilitating conditions depends on using experimental models and human systems to better understand functional interactions between innate immunity and enteric microbes that determine differentiation and activation of effector vs. regulatory T cell subsets in mucosal tissues. We hypothesize that subsets of the commensal microbiota preferentially activate protective vs. destructive innate signaling pathways that integratively activate mucosal innate and antigen presenting cells to secrete cytokines that promote regulatory vs. effector T cell responses. These interacting bacterially- activated innate and adaptive pathways mediate homeostatic vs. effector immune responses and can be manipulated for therapeutic purposes. This hypothesis will be addressed through synergistic efforts of six fully integrated investigators with complementary expertise in innate immunity and host-microbiota interactions, facilitated by two highly utilized cores. Project 1 (Jenny Ting): "NOD-like receptors in intestinal inflammation". Project 2 (Balfour Sartor): "Role of IL-10 in APC regulation of protective vs. pathogenic T cell responses to commensal bacteria". Project 3 (Scott Plevy): "Macrophage IL-10 and IL-12 regulation by the enteric microbiota in intestinal inflammation ". Project 4 (John Rawls): "Microbial regulation of systemic neutrophil function". The Project Leaders will be supported by two highly interactive cores that have already facilitated collaborative research. Core A: Gnotobiotic and Transgenic Rodent and Zebrafish Core (Core Co- Directors, Drs. Sartor and Rawls). Core B: Human Tissue and Genomics Core (Co-Directors, Drs. Scott Plevy, Hans Herfarth and Shehzad Sheikh). The investigators, facilitated by Cores, are poised to accelerate the understanding of how the innate immune system interacts with the enteric microbiota in health and disease. This knowledge could have a major public health impact upon IBD and the numerous disorders that result from dysregulated innate immune interactions with enteric microbiota.