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

总体摘要 遗传易感宿主的粘膜免疫系统、上皮屏障和肠道之间的相互作用 微生物群有助于人类炎症性肠病 (IBD) 的发病机制。 IBD 的发病机制以及最终治愈和预防这些慢性、使人衰弱的疾病取决于 创新地使用实验动物模型和人体组织样本的转化研究，以更好地 了解粘膜免疫调节、上皮反应和 来自人类 IBD 的证据支持肠道微生物决定肠道稳态与炎症。 假设炎症是由 T 细胞对肠道子集的过度反应引起的 我们的主要目标是粘膜屏障功能有缺陷的遗传易感宿主中的微生物群。 修订后的竞争性更新将应用多学科、机械化的转化方法来确定 介导免疫和上皮稳态并决定的分子因素和细菌种类 这些保护机制的丧失如何导致 IBD。我们总体的两部分假设是：（i）双向。 肠道微生物亚群与适应性（T 细胞和 B 细胞）免疫和上皮信号传导之间的相互作用 途径维持粘膜稳态，以及 (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 患者的临床相关子集。 重点关注“粘膜防御”，涉及微生物“串扰”和免疫上皮相互作用。 项目项目解决了这些相互作用的基本和转化方面以及它们如何影响临床 IBD 异质性。我们将通过两个将四个独立但又相互联系的总体目标来检验我们的假设。 错综复杂的集成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稳态 预防和慢性肠道炎症。 目标 2：利用综合转录组学和微生物分析对 IBD 亚群进行分子表型分析。 该计划项目利用了具有广泛专业知识的多学科研究人员之间的互动 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。 5年来，这个综合小组已经加深了对IBD相关机制的理解 使用精细的实验疾病模型研究发病机制以及这些途径如何影响人类 IBD。 更新使该小组能够推进这些研究，以改善 IBD 患者的管理 个性时尚。 1