A network model of the gut host-microbe ecosystem in Inflammatory Bowel Disease

炎症性肠病肠道宿主微生物生态系统的网络模型

基本信息

批准号：
9315812
负责人：
RICHARD A BONNEAU
金额：
$ 63.61万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-25 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9315812
关键词：
American Anti-Inflammatory Agents Anti-inflammatory Antibody Therapy Arthritis Autoimmune Diseases Autoimmune Process Bacteria Cell Differentiation process Cell physiology Cells Chromatin Chronic Colitis Colon Communities Data Data Collection Data Set Databases Defect Dendritic Cells Development Disease Disease Progression Ecological Change Ecology Ecosystem Elements Epithelial Epithelial Cells Etiology Event Evolution Experimental Designs FAIRE sequencing Flow Cytometry Follow-Up Studies Gene Expression Regulation Genes Genetic Genetic Transcription Genetic Variation Genetic study Genomics Helicobacter hepaticus Homeostasis Human Human Genetics Immune Immune response Immune signaling Immune system Inflammation Inflammatory Inflammatory Bowel Diseases Interleukin-10 Internet Intervention Intestines Lamina Propria Lead Learning Measurement Measures Microbe Modeling Molecular Molecular Models Mouse Strains Mucosal Immunity Multiple Sclerosis Mus Mutant Strains Mice Mutation Orthologous Gene Pathogenesis Pathology Pathway interactions Phenotype Play Population Positioning Attribute Recombinant DNA Regulation Regulatory T-Lymphocyte Resources Rheumatoid Arthritis Role Series Side Signal Pathway Signal Transduction Site Small Intestines Surveys Symbiosis Testing Time Tissues antimicrobial peptide cell type cost cytokine design experimental study genome wide association study germ free condition gut microbiome gut microbiota human disease immune function immunoregulation interleukin-23 intestinal epithelium microbial microbial community microbial host microbiome microbiota molecular modeling molecular scale mouse model network models public health relevance response tool transcriptome sequencing transcriptomics

项目摘要

DESCRIPTION (provided by applicant): Recent studies highlight a crucial role for gut mucosal immunity in both gut-proximal autoimmune diseases (Inflammatory Bowel Disease (IBD)) and in those involving extraintestinal compartments (rheumatoid arthritis and multiple sclerosis). The development of autoimmune disease involves the coordination of multiple gut- resident cell types and the gut microbiome. On the host side, immune cells and intestinal epithelium orchestrate gut microbial homeostasis via secretion of effector cytokines, antimicrobial peptides, and other molecules. Microbiota are also important modulators of immune responses, influencing the differentiation and function of immune cell populations. We propose an experimental design that combines IBD-relevant perturbations of host and microbiota. Cell abundance (immune cell and microbiota, Aim 1) and genomic measurements (microbial and host cell transcriptomics, Aim 2) will be combined into an integrated experimental design that will allow us to connect ecological changes in the gut to underlying molecular events in bacteria and host immune cells. We will combine three host perturbations (inhibition of ROR�t, IL-10 and IL- 23) with the introduction of two microbes that induce IBD-relevant phenotypes (Segmented Filamentous Bacteria (SFB) and Helicobacter hepaticus (Hh)) into specific pathogen free mice (mice with "normal" microbiomes). SFB adheres to the small intestinal epithelium and causes the expansion of Th17 cell populations in the lamina propria, influencing colitis, arthritis- and MS-relevant phenotypes. The commensal Hh promotes an anti-inflammatory immune response to limit its own gut colonization and only induces colitis-like pathologies in mouse strains with disrupted immune function. Hh-dependent murine colitis mirrors human IBD, where otherwise harmless gut microbial perturbations lead to chronic intestinal dysbiosis in genetically immune-deficient hosts. SFB and Hh interact with IL-23 and IL-10 signaling pathways (both strongly implicated in IBD pathogenesis). Blockade of IL-23 signaling contributes to the efficacy of IL-12p40 antibody therapy for IBD and genome-wide association studies confirm a central role for IL-23R in colitis. In humans mutations in IL10R are associated with IBD and IL-10 signaling deficiency in mice leads to spontaneous microbiome- dependent colitis upon Hh colonization. Our matrix of host and immune perturbations will allow us to explore distinct complementary IBD-relevant host responses. We will focus on human-relevant mechanisms by combining our results with existing databases of human genetic variations associated with IBD and autoimmune disease to select host genes that can then be further studied in mouse models along with relevant bacteria and their products (the intersection of our host regulatory network and the set of human orthologs with IBD association, Aim 3). Completion of our study will result in a new quantitative understanding of the large network of interactions between the immune system and the microbiome and will identify molecular mechanisms relevant for designing new interventions for human inflammatory bowel disease.

描述（通过应用程序提供）：最近的研究突出了肠粘膜免疫学在肠道粘膜免疫学中的关键作用，在肠道疾病自身免疫性疾病（炎症性肠病（IBD））以及涉及的肠外室（类风湿关节炎和多发性硬化症）中的至关重要。自身免疫性疾病的发展涉及多种肠道细胞类型和肠道微生物组的协调。在宿主方面，免疫细胞和肠上皮通过分泌效应细胞因子，抗菌胡椒和其他分子来编排肠道微生物稳态。微生物群也是免疫复杂的重要调节剂，会影响免疫复杂的分化和功能。我们提出了一种实验设计，结合了与IBD相关的宿主和微生物群的扰动。细胞摘要（免疫细胞和微生物群，AIM 1）和基因组测量（微生物和宿主细胞转录组学，AIM 2）将合并为综合的实验设计，这将使我们能够将肠道的生态变化与细菌和宿主免疫球体中的分子事件联系起来。我们将结合三个宿主扰动（抑制ROR。，IL-10和IL-23），并引入两个诱导IBD相关表型的微生物（分段丝状细菌（SFB）（SFB）和甲型化肝杆菌（HH））中的三个微生物（分段丝状细菌（SFB）（HH））中，将其诱导到特定的病原体纯粹的病原体（与特定的病原体小鼠（伴有与“正常” Microbiomes））中。 SFB粘附在小肠上皮上，并导致Th17细胞种群在椎板上的膨胀，影响结肠炎，关节炎和与MS相关的表型。共生HH促进了一种抗炎免疫响应，以限制其自身的肠道定植，并且仅诱导与免疫功能干扰的小鼠菌株中的结肠炎病理。 HH依赖性鼠类结肠炎反映了人类IBD，否则无害的肠道微生物扰动会导致遗传免疫缺陷型宿主的慢性肠道性失调。 SFB和HH与IL-23和IL-10信号通路相互作用（在IBD发病机理中都强烈暗示）。 IL-23信号传导的阻断有助于IL-12P40抗体治疗对IBD和全基因组关联研究的效率，这证实了IL-23R在结肠炎中的核心作用。 IL10R中的人类突变与小鼠的IBD和IL-10信号传导缺乏有关，导致HH定殖时具有赞助的微生物组依赖性结肠炎。我们的主机和免疫扰动矩阵将使我们能够探索不同的完整IBD相关的主机响应。我们将通过将结果与与IBD和自身免疫性疾病相关的人类遗传变异的现有数据库相结合，以选择宿主基因，从而选择宿主基因，然后在小鼠模型中进一步研究宿主基因，以及相关细菌及其产品（我们的宿主调节网络的相互作用以及人类正交与IBD Cossoction的相关细菌相交）。我们的研究的完成将导致对免疫系统与微生物组之间大型相互作用网络的新定量了解，并将确定与设计针对人类炎症性肠病的新干预措施相关的分子机制。