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

识别介导粘膜稳态并确定 IBD 表型的微生物、上皮细胞和免疫细胞相互作用

• 批准号: 10642786
• 负责人: Ryan B Sartor
• 金额: $ 185.98万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-19 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10642786
• 关键词: Address; Adult; Affect; Animal Experimentation; Anti-Inflammatory Agents; B-Lymphocyte Subsets; B-Lymphocytes; Bacteria; Biological Models; Cell Communication; Cell Separation; Cell physiology; Cells; Childhood; Chronic; Clinical; Clinical Data; Coculture Techniques; Colitis; Computational Biology; Coupled; Crohn' s disease; Development; Disease; Disease Outcome; Disease Progression; Disease model; ELF3 gene; Enteral; Epithelial Cells; Epithelium; Equilibrium; Excision; Experimental Animal Model; Experimental Models; Face; Formalin; Fresh Tissue; Functional disorder; Genes; Genetic Engineering; Genetic Transcription; Genomics; Gnotobiotic; HNF4A gene; High-Throughput Nucleotide Sequencing; Homeostasis; Human; Immune; Immune Tolerance; Immune response; Immunofluorescence Immunologic; Immunologics; Immunology; Individual; Inflammation; Inflammatory Bowel Diseases; Interleukin-10; Intestines; Lamina Propria; Link; Mediating; MicroRNAs; Microbe; Microbiology; Molecular; Molecular Biology; Molecular Profiling; Mucosal Immune System; Mucous Membrane; Mus; Myeloid Cells; Natural History; Operative Surgical Procedures; Organoids; Outcome; Paraffin Embedding; Pathogenesis; Pathway interactions; Patients; Phenotype; Postoperative Period; Predisposition; Process; Publications; RNA; Recurrence; Recurrent disease; Research; Research Personnel; Resources; Role; Sampling; Scientist; Shotguns; Signal Pathway; Small RNA; System; T cell response; T-Lymphocyte; Technology; Testing; Tissue Embedding; Tissue Sample; Tissues; Translational Research; Ulcerative Colitis; Validation; Zebrafish; career development; clinical phenotype; clinically actionable; clinically relevant; cohort; crosslinking and immunoprecipitation sequencing; cytokine; data sharing; disease heterogeneity; disease phenotype; disorder subtype; experience; experimental study; follow-up; functional genomics; gut inflammation; gut microbiota; human tissue; immunoregulation; improved; innovation; intestinal epithelium; intestinal homeostasis; metabolomics; metagenomic sequencing; microbial; microbiota; microorganism interaction; molecular diagnostics; molecular phenotype; multidisciplinary; novel; pathogenic microbe; pediatric patients; predict clinical outcome; prevent; prognostic indicator; programs; protective pathway; rRNA Genes; receptor; response; transcription factor; transcriptome sequencing; transcriptomics; translational approach; translational study

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

总体抽象 一般易感宿主的粘膜免疫系统，上皮屏障并进入的相互作用 微生物群有助于人类炎症性肠病（IBD）的发病机理。解决 IBD的发病机理，并最终治愈并防止这些慢性，使人衰弱的条件取决于 实验动物模型的创新使用和人体组织样品中的转化研究以更好 了解粘膜免疫调节，上皮反应和 确定肠内稳态与创新的肠道微生物。人类IBD支持的证据 炎症是由对肠道的过度攻击性T细胞反应引起的假设 一般易感宿主的微生物群具有有缺陷的粘膜屏障功能。我们的主要目标 修订的竞争更新是应用多学科的机械转化方法来识别 介导免疫学和上皮稳态并确定的分子因子和细菌物种 这些受保护机制的损失如何导致IBD。我们的总体两部分假设是：（i）双向 肠道微生物子集与适应性（T和B细胞）免疫和上皮信号之间的相互作用 途径保持粘膜稳态和（ii）这些免疫，上皮途径和微生物特征 预测疾病结果并确定IBD患者临床相关的子集。我们的翻译研究 专注于“粘膜防御”，涉及微生物“串扰”和免疫上皮相互作用。这 计划项目解决这些相互作用的基本和翻译方面及其如何影响临床 IBD异质性。我们将通过两个链接四个独立的总体目标来测试我们的假设 复杂的整合项目和两个尖端的核心。 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稳态 并防止慢性肠炎。 AIM 2：将集成的转录组学和微生物分析用于分子表型IBD子集。 该计划项目将大量的跨学科研究人员的互动资源具有广泛的专业知识 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。只是 5年，这个综合小组已经提高了对IBD涉及机制的理解 使用精制实验疾病模型的发病机理以及这些途径如何影响人IBD。 续签允许该小组进步这些研究，以改善IBD患者的管理 个性化的时尚。 1