Mechanisms of gut epithelial DUOX-mediated intestinal homeostasis

肠道上皮DUOX介导的肠道稳态机制

• 批准号: 10090590
• 负责人: Helmut F Grasberger
• 金额: $ 49.77万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10090590
• 关键词: Address; Adherence; Adherent Culture; Bacteria; Bacterial Attachment Site; Bacterial Translocation; Biopsy; Caco-2 Cells; Cell Line; Cells; Childhood; Chronic; Colon Carcinoma; Containment; Crohn' s disease; Data; Diabetes Mellitus; Disease; Enzyme Activation; Enzymes; Epithelial; Epithelial Cells; Event; Fatty Liver; Foundations; Gastrointestinal tract structure; Gut Mucosa; Homeostasis; Host Defense; Human; Hydrogen Peroxide; Immune; Immune response; Impairment; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-10; Intestines; Lead; Life; Link; Liver diseases; Lysosomes; MAP Kinase Gene; Mediating; Membrane; Metabolic syndrome; Microbe; Mucosal Immunity; Mucous Membrane; Mus; Mutation; NADPH Oxidase; Obesity; Outcome; Oxidases; Oxidation-Reduction; Paracrine Communication; Pathogenesis; Patients; Penetration; Play; Predisposition; Prevention approach; Publishing; Reaction; Reactive Oxygen Species; Research; Respiratory Burst; Role; Salmonella; Signal Pathway; Signal Transduction; Supporting Cell; Surface; System; Testing; Therapeutic Intervention; Time; Vacuole; Work; base; disorder prevention; early onset; enteric pathogen; foodborne infection; functional loss; gastrointestinal epithelium; gene induction; gut bacteria; gut microbiota; immune activation; inflammatory disease of the intestine; inflammatory milieu; insight; interleukin-22; intestinal epithelium; intestinal homeostasis; loss of function; loss of function mutation; macrophage; monolayer; novel strategies; p38 Mitogen Activated Protein Kinase; paracrine; pathogen; prevent; preventive intervention; response; treatment planning

PROJECT SUMMARY/ABSTRACT A monolayer of gut epithelial cells covers the intestinal lumen preventing an overt immune response against the normal gut microbiota, while at the same time controlling infection with potentially life-threatening pathogens. Breakdown of this homeostatic relationship can lead to foodborne infections and chronic intestinal inflammation. Reactive oxidative species (ROS) play a critical role in mucosal host defense but also contribute to the inflammatory milieu. The protective host defense role of the classical NOX2/gp91phox NADPH oxidase, responsible for the oxidative burst reaction of macrophages, has been extensively researched, but the role of another NADPH oxidase, dual oxidase (DUOX) is less clear. Our long-term objective is to define the role of DUOX2, the only form of DUOX expressed in the gut epithelium, in epithelial defense to maintain mucosal homeostasis. The objective here is to determine how DUOX2 can protect epithelial cells from invasive bacteria that produce antioxidative enzymes to shield themselves from H2O2. Our hypothesis is that activation of DUOX2 by bacterial attachment is critical for proper handling of engulfed bacteria to maintain microbe- host homeostasis. The rationale for the proposed research is that, once it is known how DUOX2 orchestrates mucosal host defense in the intestinal epithelium, specific pharmacotherapeutics can be selected to enhance DUOX-mediated bacterial handling, resulting in new approaches to the prevention and treatment of a variety of GI disorders associated with increased bacterial translocation. We will test our central hypothesis and, thereby, accomplish the objective of this application by pursuing the following specific aims: 1. Investigate the mechanisms of DUOX2 induction by mucosa-associated bacteria, 2. Define the role of DUOX2 in the cell-autonomous containment of intestinal pathogens. 3. Study the implications of DUOX2 deficiency for susceptibility to IBD. The expected outcomes, the proposed work is expected to elucidate a mechanistic framework how DUOX2 is activated in response to bacteria-epithelial contact, supports cell- autonomous inactivation of intracellular bacteria, and, thereby, maintains immune homeostasis. Such results are expected to have an important positive impact because this immune mechanism is highly likely to provide new targets for preventative and therapeutic interventions for diseases associated with dysregulated microbe- intestinal interaction (e.g., IBD, IBS, colon cancer) in addition to fundamentally advancing the fields of gut mucosal immunity. It will also provide much-needed insight into the pathogenesis of IBD linked to DUOX2 LOF and thus the foundation to better strategize a treatment plan for these patients.

项目摘要/摘要 肠道上皮细胞的单层覆盖肠腔，以防止对 正常的肠道微生物群，同时控制感染潜在威胁生命 病原体。这种稳态关系的崩溃会导致食源性感染和慢性肠道 炎。反应性氧化物种（ROS）在粘膜宿主防御中起关键作用，但也有贡献 到炎症环境。经典NOX2/GP91PHOX NADPH氧化酶的保护性宿主防御作用， 负责巨噬细胞的氧化爆发反应，已经进行了广泛的研究，但是 另一个NADPH氧化酶，双重氧化酶（DUOX）不太清楚。我们的长期目标是定义 duox2，是肠道上皮中表达的唯一形式，在上皮防御中保持粘膜 稳态。这里的目的是确定DUOX2如何保护上皮细胞免受侵入性细菌 产生抗氧化酶以使自己免受H2O2的侵害。我们的假设是激活 细菌附着的DUOX2对于正确处理吞噬细菌以维持微生物至关重要 主持稳态。拟议的研究的理由是，一旦知道Duox2如何编排 可以选择肠上皮的粘膜宿主防御，可以选择特定的药物治疗剂以增强 Duox介导的细菌处理，从而为预防和治疗一种新方法 与细菌易位增加有关的GI疾病。我们将检验我们的中心假设，并 因此，通过追求以下特定目标来实现此应用程序的目标：1。 粘膜相关细菌DUOX2诱导的机制，2。 肠道病原体的细胞自主遏制。 3。研究duox2的含义 缺乏对IBD的敏感性。预期的结果，预计拟议的工作将阐明 机械框架如何响应细菌 - 上皮接触而激活DUOX2，支持细胞 自主的细胞内细菌失活，从而保持免疫稳态。这样的结果 预计会产生重要的积极影响，因为这种免疫机制极有可能提供 与失调的微生物相关的疾病预防和治疗干预措施的新目标 肠相互作用（例如IBD，IBS，结肠癌）除了从根本上推进肠道领域 粘膜免疫。它还将提供急需的洞察力，以了解与DUOX2 LOF相关的IBD的发病机理 因此，为这些患者更好地制定治疗计划的基础。