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

• 批准号: 9349486
• 负责人: Hiutung Chu
• 金额: $ 8.72万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-08 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9349486
• 关键词: Adverse effects; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antigen Presentation; Antigens; Autoimmune Process; Autophagocytosis; Award; Bacteria; Bacteroides fragilis; Biology; Cell physiology; Cells; Chronic; Clinical Research; Colitis; Crohn' 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; Inflammatory disease of the intestine; Innate Immune Response; Interleukin-10; Intestinal Diseases; Intestines; Knock-out; Knowledge; Laboratories; Lead; Link; MHC Class II Genes; Mediating; Medical; Membrane; Mentors; Microbe; Modeling; Monozygotic twins; 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; Symbiosis; System; T-Lymphocyte; Testing; Therapeutic; Training; Ulcerative Colitis; United States; Variant; Vesicle; Work; antigen processing; curative treatments; cytokine; evidence base; fascinate; gene environment interaction; gene product; genetic risk factor; genome wide association study; gut microbiome; gut microbiota; host-microbe interactions; immune health; immune system function; immunoregulation; innovation; insight; killings; microbial; microbiome; mouse model; novel; particle; pathogenic bacteria; pre-clinical research; prevent; probiotic therapy; programs; response; risk variant; social; tissue culture

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).

项目摘要/摘要 免疫系统的失调是许多自身免疫性和炎症性疾病的基础。与 人类基因组，肠道菌群调节免疫系统的发育和功能， 调节促和抗炎反应之间的平衡。大量证据 基于临床前和临床研究表明，肠道微生物在炎症肠中起关键作用 疾病（IBD），一个特发性肠道疾病家族，患病率增加和治疗有限 选项。单卵双胞胎的一致性率为30-40％，暗示基因环境相互作用。 基因组广泛的关联研究已经实施了大约200个易感性的地方 与IBD相关。许多变体编码参与微生物识别和免疫组织化学的基因， 提示宿主 - 微生物相互作用可以调节免疫健康与炎症之间的平衡 疾病。自噬途径基因的多态性（例如ATG16L1）和模式识别 与自噬相关的接收器（例如NOD2）代表了一些最显着的效应大小 在IBD易感性中。此外，大量研究重点是研究ATG16L1和 小鼠模型和人类细胞中的NOD2，并确定了基因产物在感测和杀死中的作用 致病微生物。因此，当前的理解表明IBD可能是由于突变引起的 损害对致病细菌的免疫力，导致长期暴露于激活的微生物产物 不受控制的炎症。在此，我提出了有益的肠道细菌的新发现 需要ATG16L1和NOD2来促进小鼠和人类细胞中的抗炎反应，而小鼠 在这些基因中删除的基因不受脆弱芽孢杆菌的侵害。我提出了一个新颖的，非冗余的角色 以前在识别和杀死致病细菌的基因 - 即通用中的突变 与IBD相关的途径导致对微生物组的有益分子的识别有缺陷。我的 假设是，ATG16L1中的遗传缺陷可能通过不“传感”并响应受保护的遗传缺陷会导致IBD 有益肠道细菌的信号。我将以三个特定目的测试我的假设，其中包括：1）定义 Fragilis免疫调节所需的细胞途径； 2）确定ATG16L1作用机理 在调节性T细胞诱导过程中，脆弱的链球菌诱导； 3）确定是否需要NOD2进行中介 脆弱链球菌在小鼠和人类系统中的有益作用。换句话说，缺乏灵敏度和 对抗炎细菌信号反应可能是慢性肠道注射的危险因素。这 Sarkis Mazmanian博士将考虑该奖项的培训（K99）阶段，并将促进过渡 我针对独立研究者（R00）的研究计划。