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

整体的抽象

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

A machine learning approach identifies 5-ASA and ulcerative colitis as being linked with higher COVID-19 mortality in patients with IBD.

• DOI: 10.1038/s41598-021-95919-2
• 发表时间: 2021-08-13
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Roy S;Sheikh SZ;Furey TS
• 通讯作者: Furey TS

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