Microbiota, Tertiary Lymphoid Structures and Chronic Inflammation in the Human Gut

微生物群、三级淋巴结构和人类肠道慢性炎症

基本信息

批准号：
10154604
负责人：
Milena Bogunovic
金额：
$ 25.39万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-06 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10154604
关键词：
Address Adult Affect Animal Model Antibody Response Antigen-Presenting Cells Antigens Area Atherosclerosis Autoimmune Autoimmune Diseases Autoimmunity B-Lymphocytes Binding Biology Cell Fraction Cell Separation Cell model Cell surface Cells Chronic Chronic Disease Chronic Gastritis Clinical Coin Colitis Collaborations Colorectal Cancer Crohn&apos s disease Data Set Defect Dendritic Cells Development Disease Drug or chemical Tissue Distribution Excision Flow Cytometry Functional disorder Future Gastroenterology Gastrointestinal tract structure Gene Expression Generations Genetic Graft Rejection Heterogeneity Human Immune Immune response Immunoglobulin A Immunoglobulin G Immunology Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Intestines Life Link Lymphoid Malignant Neoplasms Metagenomics Methodology Microbe Microscopy Molecular Mononuclear Mucous Membrane Mus Operative Surgical Procedures Organ Outcome Pathogenesis Pathogenicity Pathology Pathway Analysis Patients Phagocytes Phenotype Plasma Cells Population Positioning Attribute Prognostic Factor Publications Publishing Reaction Reporting Resources Salmonella Salmonella infections Science Shotguns Site Specificity System T-Lymphocyte Testing Tissues Ulcerative Colitis Viral bacteriome cancer type checkpoint therapy commensal microbes gastrointestinal graft vs host disease gut microbiota host-microbe interactions human model lymph nodes macrophage medical schools microbial microbiota mucosal site multidisciplinary multiple omics novel therapeutic intervention novel therapeutics pathobiont response salmonella colitis secondary lymphoid organ tertiary lymphoid organ transcriptome sequencing virome

项目摘要

PROJECT SUMMARY Tertiary lymphoid structures (TLS) are ectopic disorganized lymphoid aggregates with the cellular composition resembling secondary lymphoid organs. Although the exact function of TLS remains elusive, the accumulated evidence suggests that TLS significantly contribute to the pathogenesis of chronic disorders including autoimmune and inflammatory diseases, graft versus host disease, transplant rejection, and various types of cancer. Therefore, better understanding of the composition of TLS and specificity of the immune response that they initiate in the context of a specific disease may help decode the disease pathogenesis and provide novel therapeutic strategies. Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), is thought to result from the dysregulated immune response to commensal microbes driven by a convergence of genetic, environmental and microbial factors. Studies in humans and animal models indicate that IBD pathogenesis is associated with dysregulated mononuclear phagocyte (MP) system and abnormal T and B cell responses. We recently identified the mechanisms that drive TLS development in mice with Salmonella colitis. In this new study we will take advantage of our expertise, established collaboration and clinical resources available at UMass Medical School (UMMS) to understand the mechanisms that drive TLS development and function in human IBD. Our overarching hypothesis is that TLS in IBD are dysregulated towards a preferential generation of local proinflammatory IgG response instead of IgA and are induced by specific inflammatory MP subsets in response to pathobionts that colonize the mucosa. To test the hypothesis, we are going to analyze intestinal surgical resections from patients with IBD by applying a combination of multi-OMICs approaches. Our actively collaborating multi-disciplinary team that consists of experts in MP biology, computational biomedicine, bacterial microbiome, virome, gastroenterology and clinical GI pathology is uniquely positioned to address the following specific aims: Aim 1. Establish cellular composition and predict intercellular interactions in TLS in human IBD; Aim 2. Identify pathobionts that drive TLS formation via MP activation in human IBD. As the outcome of this project, we will establish a model of cell-cell and cell-microbe interactions and identify key regulatory molecules required for development of intestinal TLS in human IBD. Short term, these results will provide a basis for our future R01 proposal that will test computational predictions of host-microbial interactions and link them to disease pathogenesis with the underlying rationale to identify novel therapeutic avenues aimed at TLS in IBD. In the long term, information and methodology gained from this study will be applied to other inflammatory and autoimmune conditions as well as cancers in which TLS formation is evident.

项目概要三级淋巴结构 (TLS) 是具有细胞成分的异位紊乱淋巴聚集体类似于次级淋巴器官，尽管 TLS 的确切功能仍然难以捉摸，但累积的有证据表明 TLS 显着促进慢性疾病的发病机制，包括自身免疫性疾病和炎症性疾病、移植物抗宿主病、移植排斥和各种类型的因此，更好地了解 TLS 的组成和免疫反应的特异性。它们在特定疾病的背景下启动可能有助于解码疾病的发病机制并提供新的治疗策略。炎症性肠病 (IBD)，包括克罗恩病 (CD) 和溃疡性结肠炎 (UC)，被认为是由于对共生微生物的免疫反应失调造成的，这种免疫反应是由多种因素共同驱动的遗传、环境和微生物因素对人类和动物模型的研究表明 IBD。发病机制与单核吞噬细胞 (MP) 系统失调以及异常 T 和 B 细胞有关我们最近确定了沙门氏菌结肠炎小鼠 TLS 发育的机制。在这项新研究中，我们将利用我们的专业知识、既定的合作和临床资源可在麻省大学医学院 (UMMS) 了解驱动 TLS 开发的机制和我们的总体假设是，IBD 中的 TLS 失调，偏向于优先性。产生局部促炎 IgG 反应而不是 IgA，并由特定的炎症 MP 诱导为了检验这一假设，我们将进行分析。通过结合多组学方法对 IBD 患者进行肠道手术切除。积极合作的多学科团队，由 MP 生物学、计算生物医学、细菌微生物组、病毒组、胃肠病学和临床胃肠道病理学具有独特的地位来解决以下具体目标：目标 1. 建立人类 IBD 中 TLS 的细胞组成并预测细胞间相互作用；目标 2. 识别在人类 IBD 中通过 MP 激活驱动 TLS 形成的病原体。作为该项目的成果，我们将建立细胞-细胞和细胞-微生物相互作用的模型，短期内，这些是确定人类 IBD 肠道 TLS 发育所需的关键调节分子。结果将为我们未来的 R01 提案提供基础，该提案将测试宿主微生物的计算预测相互作用并将它们与疾病发病机制联系起来，并通过潜在的原理来确定治疗新药从长远来看，从这项研究中获得的信息和方法将是针对 IBD 的 TLS 的途径。适用于其他炎症和自身免疫性疾病以及 TLS 形成明显的癌症。