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: 10723727
• 负责人: Ryan B Sartor
• 金额: $ 3.99万
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10723727
• 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 肠道微生物群参与人类炎症性肠病（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性疾病取决于 创新使用实验动物模型和人体组织样本转化研究， 理解粘膜免疫调节、上皮反应和 肠道微生物决定肠道内稳态与炎症。来自人类IBD的证据支持 假设炎症是由过度积极的T细胞反应导致的肠上皮细胞亚群 在具有缺陷的粘膜屏障功能的遗传易感宿主中的微生物群。我们的主要目标是 修订后的竞争更新是应用多学科，机械翻译的方法，以确定 介导免疫和上皮稳态的分子因子和细菌种类， 这些保护机制的丧失如何导致IBD。我们的总体两部分假设是：（一）双向 肠道微生物亚群与适应性（T和B细胞）免疫和上皮信号传导之间的相互作用 途径维持粘膜稳态，和（ii）这些免疫、上皮途径和微生物谱 预测疾病结果并识别IBD患者的临床相关子集。我们的翻译研究 重点是“粘膜防御”，包括微生物“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。我们将通过两个总体目标来测试我们的假设，这两个目标将四个独立的，但 错综复杂的综合项目和两个尖端的核心。 目的1：确定正常粘膜免疫-微生物相互作用如何促进粘膜稳态 预防慢性肠道炎症。 目的2：使用整合转录组学和微生物谱分析对IBD亚群进行分子表型分析。 该计划项目利用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。短短 5年来，这个综合小组已经提高了对IBD相关机制的理解 使用精细的实验疾病模型研究IBD的发病机制以及这些途径如何影响人类IBD。 更新允许该组推进这些研究，以改善IBD患者的管理， 个性化的时尚 1

项目成果

Increased colonic expression of ACE2 associates with poor prognosis in Crohn's disease.

• DOI: 10.1038/s41598-021-92979-2
• 发表时间: 2021-06-29
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Toyonaga T;Araba KC;Kennedy MM;Keith BP;Wolber EA;Beasley C;Steinbach EC;Schaner MR;Jain A;Long MD;Barnes EL;Herfarth HH;Isaacs KL;Hansen JJ;Kapadia MR;Guillem JG;Gulati AS;Sethupathy P;Furey TS;Ehre C;Sheikh SZ
• 通讯作者: Sheikh SZ

Harnessing the Power of Posttranscriptional Gene Silencing in Crohn's Disease.

利用转录后基因沉默的力量治疗克罗恩病。

• DOI: 10.1038/ctg.2016.5
• 发表时间: 2016
• 期刊: Clinical and translational gastroenterology
• 影响因子: 3.6
• 作者: Abdalla,Maisa;Sheikh,ShehzadZ
• 通讯作者: Sheikh,ShehzadZ

Multiomic analysis of microRNA-mediated regulation reveals a proliferative axis involving miR-10b in fibrolamellar carcinoma.

• DOI: 10.1172/jci.insight.154743
• 发表时间: 2022-06-08
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Francisco, Adam B.;Kanke, Matt;Massa, Andrew P.;Dinh, Timothy A.;Sritharan, Ramja;Vakili, Khashayar;Bardeesy, Nabeel;Sethupathy, Praveen
• 通讯作者: Sethupathy, Praveen

Opioid Toxicity in Inflammatory Bowel Disease Patients Likely Includes Direct Enterocyte Effects That Exacerbate Disease.

炎症性肠病患者的阿片类药物毒性可能包括加剧疾病的直接肠上皮细胞作用。

• DOI: 10.1016/j.cgh.2018.05.017
• 发表时间: 2018
• 期刊: Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
• 作者: Goldsmith,JasonR;Sartor,RBalfour
• 通讯作者: Sartor,RBalfour

Roles for Intestinal Bacteria, Viruses, and Fungi in Pathogenesis of Inflammatory Bowel Diseases and Therapeutic Approaches.

肠道细菌、病毒和真菌在炎症性肠病发病机制和治疗方法中的作用。

• DOI: 10.1053/j.gastro.2016.10.012
• 发表时间: 2017-03
• 期刊: Gastroenterology
• 影响因子: 29.4
• 作者: Sartor RB;Wu GD
• 通讯作者: Wu GD