Identifying Microbial, Epithelial and Immune Cell Interactions that Mediate Mucosal Homeostasis and Determine IBD Phenotypes

总体摘要 遗传易感宿主的黏膜免疫系统、上皮屏障和肠道之间的相互作用 微生物区系参与了人类炎症性肠病(IBD)的发病机制。解决 IBD的发病机制以及最终治愈和预防这些慢性、衰弱的疾病取决于 创新性地使用实验动物模型和人体组织样本的翻译研究，以更好地 了解粘膜免疫调节、上皮反应和粘膜免疫之间的功能和机制的相互作用 决定肠道动态平衡与炎症的肠道微生物。来自人类IBD的证据支持 一种假设，认为炎症是由过度侵略性的T细胞对肠道某一亚群的反应引起的 具有黏膜屏障功能缺陷的遗传易感宿主中的微生物区系。我们的主要目标是 修订后的竞争更新将应用多学科、机械化的转换方法来确定 调节免疫和上皮动态平衡的分子因子和细菌种类 这些保护机制的丧失是如何导致IBD的。我们的总体两部分假设是：(I)双向 肠道微生物亚群与适应性(T和B细胞)免疫和上皮信号的相互作用 这些途径维持粘膜的动态平衡和(Ii)这些免疫、上皮性途径和微生物谱 预测疾病结果并确定临床上相关的IBD患者亚群。我们的翻译研究 关注“粘膜防御”，包括微生物的“串扰”和免疫-上皮的相互作用。这 计划项目涉及这些交互的基本和翻译方面，以及它们对临床的影响 IBD异质性。我们将通过两个首要目标来测试我们的假设，这两个目标将四个独立的目标联系在一起 错综复杂的综合项目和两个尖端核心。 目标1：确定正常的粘膜免疫-微生物相互作用如何促进粘膜的动态平衡 并预防慢性肠炎。 目的2：利用整合转录组学和微生物图谱分析IBD亚型的分子表型。 该计划项目利用具有广泛专业知识的多学科调查人员之间的互动 微生物学、粘膜免疫学、代谢组学、基因组学、计算生物学和临床IBD。在短短的几分钟内 5年来，这个综合小组已经提高了对IBD涉及的机制的理解 使用改进的实验性疾病模型以及这些途径如何影响人类IBD的发病机制。 更新允许该小组推进这些研究，以改善对IBD患者的管理 个性化的时尚。 1

OVERALL ABSTRACT Interactions between a genetically susceptible host’s mucosal immune system, epithelial barrier and enteric microbiota contribute to the pathogenesis of human inflammatory bowel diseases (IBD). Solving the pathogenesis of IBD and ultimately curing and preventing these chronic, debilitating conditions depend on innovative use of experimental animal models and translational research in human tissue samples to better understand functional, mechanistic interactions between mucosal immune regulation, epithelial responses and enteric microbes that determine intestinal homeostasis vs inflammation. Evidence from human IBD supports the hypothesis that inflammation results from overly aggressive T cell responses to a subset of intestinal microbiota in genetically susceptible hosts with defective mucosal barrier function. Our major objectives of this revised competing renewal are to apply multidisciplinary, mechanistic translational approaches to identify molecular factors and bacterial species that mediate immunologic and epithelial homeostasis and determine how loss of these protective mechanisms result in IBD. Our overall two-part hypothesis is: (i) Bidirectional interactions between intestinal microbial subsets and adaptive (T and B cell) immune and epithelial signaling pathways maintain mucosal homeostasis and (ii) these immune, epithelial pathways and microbial profiles predict disease outcomes and identify clinically relevant subsets of IBD patients. Our translational studies focus on ‘mucosal defense’, involving microbial “crosstalk,” and immune-epithelial interactions. This Program Project addresses basic and translational aspects of these interactions and how they impact clinical IBD heterogeneity. We will test our hypotheses through two overarching aims that link four independent yet intricately integrated projects and two cutting-edge cores. Aim 1: Establish how normal mucosal immune-microbial interactions promote mucosal homeostasis and prevent chronic intestinal inflammation. Aim 2: Use integrative transcriptomics and microbial profiling to molecularly phenotype IBD subsets. This Program Project capitalizes on interactions among multidisciplinary investigators with extensive expertise in microbiology, mucosal immunology, metabolomics, genomics, computational biology and clinical IBD. In just 5 years, this integrated group has already improved understanding of mechanisms involved in IBD pathogenesis using refined experimental disease models and how these pathways impact human IBD. Renewal allows this group to advance these studies to improve management of IBD patients in an individualized fashion. 1