The Microbiome Mediates Protections from Colitis Through Pathways Linked to IBD

微生物组通过与 IBD 相关的途径介导结肠炎的保护作用

基本信息

批准号：
9902409
负责人：
Hiutung Chu
金额：
$ 24.71万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-12 至 2022-04-11
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9902409
关键词：
Affect Anti-Inflammatory Agents Antigen Presentation Antigens Autoimmune Process Autophagocytosis Award Bacteria Bacteroides fragilis Biology Cell physiology Cells Chronic Clinical Research Colitis Crohn&apos s disease Data Dendritic Cells Development Diagnosis Disease Disease susceptibility Environmental Risk Factor Equilibrium Etiology Exposure to FOXP3 gene Family Gastrointestinal tract structure Genes Genetic Genetic Polymorphism Genetic Risk Health Human Human Genome Immune Immune system Immunity Impairment Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Innate Immune Response Interleukin-10 Intestinal Diseases Intestines Knock-out Knowledge Laboratories Lead Link MHC Class II Genes Mediating Medical Membrane Mentors Modeling Monozygotic twins Mucous Membrane Mus Mutation Pathogenesis Pathogenicity Pathway interactions Patients Pattern recognition receptor Peptidoglycan Phagocytosis Phase Play Polysaccharides Prevalence Process Production Property Regulatory T-Lymphocyte Research Research Personnel Risk Factors Role Signal Transduction Surface Susceptibility Gene System T-Lymphocyte Testing Therapeutic Training Ulcerative Colitis United States Variant Vesicle Work antigen processing beneficial microorganism curative treatments cytokine evidence base fascinate gene environment interaction gene product genetic risk factor genome wide association study gut bacteria gut microbes gut microbiome gut microbiota host-microbe interactions human model immune health immune system function immunoregulation inflammatory disease of the intestine innovation insight microbial microbiome mouse model novel particle pathogenic bacteria pathogenic microbe pre-clinical research prevent probiotic therapy programs response risk variant side effect social tissue culture

项目摘要

PROJECT SUMMARY/ABSTRACT Dysregulation of the immune system underlies many autoimmune and inflammatory diseases. In concert with the human genome, the intestinal microbiota regulate development and function of the immune system, modulating the balance between pro- and anti-inflammatory responses. A considerable body of evidence based on preclinical and clinical research suggests that gut microbes play a critical role in inflammatory bowel disease (IBD), a family of idiopathic intestinal disorders with increasing prevalence and limited treatment options. Concordance rates of 30-40% among monozygotic twins implicate gene-environment interactions. Genome wide association studies have implicated roughly 200 susceptibility loci that are significantly associated with IBD. Many variants encode for genes involved in microbial recognition and immunity, suggesting host-microbe interactions may regulate the balance between immune health and inflammatory disease. Polymorphisms in genes of the autophagy pathway (e.g., ATG16L1), and in pattern recognition receptors that are associated with autophagy (e.g., NOD2), represent some of the most significant effect sizes in IBD susceptibility. Further, considerable research has focused on investigating the function of Atg16L1 and NOD2 in mouse models and human cells, and identified a role for both gene products in sensing and killing pathogenic microbes. Current understanding therefore suggest that IBD may be caused by mutations that impair immunity to pathogenic bacteria, leading to chronic exposure to microbial products that activates uncontrolled inflammation. Herein, I present new findings that beneficial gut bacteria such a Bacteroides fragilis require Atg16L1 and NOD2 to promote anti-inflammatory responses in mouse and human cells, and mice deleted in these genes are not protected from colitis by B. fragilis. I propose a novel, non-redundant role for genes previously implicated in recognition and killing of pathogenic bacteria—namely, mutations in genetic pathways linked to IBD result in defective recognition of beneficial molecules from the microbiome. My hypothesis is that genetic defects in Atg16L1 may lead to IBD by not `sensing' and responding to the protective signals of beneficial gut bacteria. I will test my hypothesis in three Specific Aims, which include: 1) defining the cellular pathway(s) required for immune regulation by B. fragilis; 2) Determining Atg16L1 mechanism of action during regulatory T cell induction by B. fragilis; 3) Establishing whether NOD2 is required for mediating the beneficial effects of B. fragilis in mouse and human systems. In other words, the absence of sensing and responding to anti-inflammatory bacterial signals may be a risk factor for chronic intestinal inflammation. The training (K99) phase of this award will be mentored by Dr. Sarkis Mazmanian, and will facilitate the transition of my research program towards an independent investigator (R00).

项目概要/摘要免疫系统失调是许多自身免疫性疾病和炎症性疾病的基础。人类基因组、肠道微生物群调节免疫系统的发育和功能，调节促炎反应和抗炎反应之间的平衡有大量证据。临床前和临床研究表明肠道微生物在炎症性肠病中发挥着关键作用疾病（IBD），一类特发性肠道疾病，患病率不断增加，但治疗方法有限同卵双胞胎中 30-40% 的一致率意味着基因与环境的相互作用。全基因组关联研究表明大约 200 个易感位点与许多变异体编码参与微生物识别和免疫的基因，表明宿主-微生物相互作用可能调节免疫健康和炎症之间的平衡自噬途径基因（例如 ATG16L1）和模式识别的多态性。与自噬相关的受体（例如 NOD2）代表了一些最显着的效应大小此外，大量研究集中在研究 Atg16L1 和 IBD 的功能上。 NOD2 在小鼠模型和人类细胞中的作用，并确定了这两种基因产物在感知和杀伤中的作用因此，目前的认识表明 IBD 可能是由以下突变引起的：损害对病原菌的免疫力，导致长期接触激活微生物的产品在此，我提出了有益的肠道细菌（例如脆弱拟杆菌）的新发现。需要 Atg16L1 和 NOD2 来促进小鼠和人类细胞以及小鼠的抗炎反应这些基因中的缺失并不能保护脆弱拟杆菌免受结肠炎的影响，我提出了一种新的、非冗余的作用。以前与识别和杀死病原菌有关的基因，即基因突变与 IBD 相关的途径导致微生物组中有益分子的识别缺陷。假设 Atg16L1 的遗传缺陷可能通过无法“感知”和对保护性反应做出反应而导致 IBD 我将在三个具体目标中检验我的假设，其中包括：1）定义脆弱拟杆菌免疫调节所需的细胞途径；2) 确定 Atg16L1 的作用机制；脆弱拟杆菌诱导调节性 T 细胞期间；3) 确定 NOD2 是否需要介导换句话说，脆弱拟杆菌对小鼠和人类系统的有益影响。对抗炎细菌信号的反应可能是慢性肠道炎症的危险因素。该奖项的培训（K99）阶段将由 Sarkis Mazmanian 博士指导，并将促进过渡我针对独立调查员（R00）的研究计划。