Host innate immune-microbial interactions and intestinal inflammation

描述(申请人提供)：宿主先天免疫系统和肠道微生物区系之间的相互作用是特发性人类炎症性肠病(IBD)发病机制中的最新事件。解决IBD的发病机制，并最终治愈和预防这些慢性、衰弱的疾病，依赖于使用实验模型和人类系统来更好地了解天然免疫和肠道微生物之间的功能相互作用，这种相互作用决定了粘膜组织中效应者和调节性T细胞亚群的分化和激活。我们假设，共生微生物区系的亚群优先激活保护性和破坏性的先天信号通路，这些信号通路整合地激活粘膜固有细胞和抗原提呈细胞，以分泌促进调节性和效应性T细胞反应的细胞因子。这些相互作用的、细菌激活的、先天的和适应性的途径介导了动态平衡对效应器的免疫反应，并可用于治疗目的。这一假说将通过六名完全整合的研究人员的协同努力来解决，他们在先天性免疫和宿主-微生物区系相互作用方面具有互补的专业知识，并由两个利用率高的核心促进。项目1(Jenny Ting)：“肠道炎症中的点状受体”。项目2(Balfour Sartor)：“IL-10在APC调节保护性和致病性T细胞对共生菌的反应中的作用”。项目3(Scott Plevy)：“肠道微生物群对肠道炎症中巨噬细胞IL-10和IL-12的调节”。项目4(John Rawls)：“全身中性粒细胞功能的微生物调节”。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协作研究。核心A：灵生和转基因啮齿动物和斑马鱼核心(核心联合董事，Sartor和Rawls博士)。核心B：人类组织和基因组学核心(联席主任，Scott Plevy博士、Hans Herfarth博士和Shehzad Sheikh)。在核心的帮助下，研究人员准备加快了解先天免疫系统如何与肠道微生物区系在健康和疾病中相互作用。这一知识可能对IBD以及由肠道微生物区系调节失调的先天性免疫相互作用引起的多种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.