Mechanisms of Duox2 variants in the pathogenesis of preclinical IBD

Duox2变异在临床前IBD发病机制中的作用

基本信息

批准号：
10752786
负责人：
Helmut F Grasberger
金额：
$ 68.47万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10752786
关键词：
Ablation Address Alleles Biopsy Cells Chronic Colitis Colon Carcinoma Defect Development Diabetes Mellitus Disease Early Diagnosis Early treatment Enterocytes Enzymes Epithelium Event Gastrointestinal tract structure Genes Genetic Genetic Epistasis Genetic Variation Gnotobiotic Gram-Negative Bacteria Granulocyte-Macrophage Colony-Stimulating Factor Growth Gut Mucosa Healthcare Homeostasis Homologous Gene Host Defense Human Hydrogen Peroxide IL17C gene Immune Immune response In Vitro Individual Inflammatory Inflammatory Bowel Diseases Integration Host Factors Investigation Link M cell Measures Mediating Metabolic syndrome Microbe Modeling Molecular Morbidity - disease rate Mucosal Immunity Mucous Membrane Mucous body substance Mus NADPH Oxidase Obesity Onset of illness Outcome Oxidases Oxidation-Reduction Pathogenesis Pathogenicity Pathway interactions Patients Phenotype Plasma Population Population Attributable Risks Predisposition Production Prognosis Proteins Regulation Research Resources Risk Risk Factors Role Signal Transduction System Testing Therapeutic Intervention Variant Work autocrine bacterial fitness disorder prevention dysbiosis fatty liver disease genetic association genetic variant genome-wide germ free condition gut bacteria gut microbes gut microbiota improved interleukin-17C interleukin-22 intestinal barrier loss of function man microbial colonization microbiota multiple omics new therapeutic target novel novel strategies overexpression pathobiont pharmacologic pre-clinical prevent preventive intervention reconstitution risk variant virulence gene

项目摘要

PROJECT SUMMARY/ABSTRACT Inflammatory Bowel Disease (IBD) is a debilitating gut disorder with significant morbidity and healthcare resource utilization. Because early diagnosis and treatment may improve the prognosis of IBD, there is an urgent need to better understand the preclinical incipient disturbance of gut microbe-epithelial homeostasis in at-risk individuals to identify novel therapeutic targets to halt disease onset, which is our long-term objective. A crucial host factor in maintaining a homeostatic relationship with the gut microbiota is Dual Oxidase 2 (DUOX2), an epithelial-specific NADPH oxidase releasing H2O2 into the supra-epithelial mucus layer. DUOX2 is highly inducible by abnormal microbial colonization and among the most robustly and consistently overexpressed genes in mucosal biopsies from patients with preclinical IBD. We previously showed a defect in DUOX2 leads to activation of compensatory epithelial defense systems in specific-pathogen-free mice and loss-of-function alleles in human populations are associated with increased susceptibility to IBD. However, the relevant mechanisms underlying this genetic association remain unclear. The objective here is to determine how DUOX2 loss-of-function genetic variants render an individual susceptible to dysbiosis and a loss of mucosal immune homeostasis leading to IBD. We hypothesize that dysregulation of IL-17C signaling is a critical pathogenic driver of DUOX2-associated IBD. The rationale for the proposed research is that, once it is known how dysregulation of IL-17C signaling in DUOX2 defective hosts contributes to pathogenesis of IBD, novel strategies can be developed to identify at-risk individuals and restore homeostasis to prevent the onset of IBD. We will test our hypothesis and, thereby, accomplish our objective by pursuing the following specific aims: 1. Determine the mechanisms of how DUOX2 loss-of-function results in microbe-dependent activation of the IL17C axis. 2. Assess the function of IL17RE-like protein, a hitherto uncharacterized IBD risk factor. 3. Investigate the role of chronic IL-17C activation in DUOX2 defective hosts as a driver of IBD pathogenesis. The expected outcome of the proposed work is a mechanistic framework of how DUOX2 variants cause an increased risk for IBD, namely by sustained activation of IL17C-mediated immune responses due to abnormal microbe-epithelial interactions. Such results are expected to have an important positive impact because understanding how DUOX2 variants contribute to IBD pathogenesis 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.

项目摘要/摘要炎症性肠病（IBD）是一种令人衰弱的肠道疾病，具有明显的发病率和医疗保健资源利用。由于早期诊断和治疗可能会改善IBD的预后，因此迫切需要更好地了解肠道微生物 - 上皮稳态的临床前初期障碍在高危个体中，可以识别出新的治疗靶标，以阻止疾病发作，这是我们的长期目标。维持与肠道菌群保持稳态关系的关键宿主因素是双重氧化酶2 （DUOX2），一种上皮特异性的NADPH氧化酶，将H2O2释放到上皮粘液层中。 duox2 由于微生物定植异常，并且在最坚固，最稳定的中是高度诱导的临床前IBD患者的粘膜活检中过表达的基因。我们以前显示出缺陷在duox2中，导致在不含特定疾病的小鼠中激活补偿性上皮防御系统人类种群的功能丧失等位基因与对IBD的敏感性增加有关。然而，这种遗传关联的基础机制尚不清楚。这里的目的是确定DUOX2功能丧失的遗传变异如何使人容易发病障碍和A 失去粘膜免疫稳态导致IBD。我们假设IL-17C的失调失调信号传导是与DUOX2相关的IBD的关键致病驱动力。提议的理由研究是，一旦知道DUOX2中有缺陷宿主中IL-17C信号传导的失调如何贡献对于IBD的发病机理，可以开发出新的策略来识别高危个人并恢复稳态以防止IBD发作。我们将检验我们的假设，从而实现我们的目标通过追求以下特定目标：1。确定DUOX2功能丧失结果的机制在IL17C轴的微生物依赖性激活中。 2。评估IL17RE样蛋白的功能，迄今为止未表征的IBD风险因素。 3。研究慢性IL-17C激活在DUOX2有缺陷宿主中的作用作为IBD发病机理的驱动力。拟议工作的预期结果是一个机械框架 DUOX2变体如何导致IBD的风险增加，即IL17C介导的持续激活由于微生物 - 上皮相互作用而引起的免疫反应。这些结果预计将有一个重要的积极影响，因为了解DUOX2变体对IBD发病机理的贡献是极有可能为与之相关的疾病的预防和治疗干预提供新目标除了根本上，微生物 - 肠相互作用失调（例如，IBD，IBS，结肠癌）促进肠粘膜免疫的领域。