Mechanisms of Duox2 variants in the pathogenesis of preclinical IBD

项目总结/摘要 炎症性肠病（IBD）是一种使人衰弱的肠道疾病，具有显著的发病率和医疗保健 资源利用由于早期诊断和治疗可改善IBD的预后， 迫切需要更好地了解肠道微生物-上皮稳态的临床前初期紊乱 在高危人群中寻找新的治疗靶点以阻止疾病发作，这是我们的长期目标。 维持与肠道微生物群的稳态关系的关键宿主因子是双氧化酶2 （DUOX 2），一种上皮特异性NADPH氧化酶，将H2 O2释放到上皮上粘液层中。DUOX2 是高度可诱导的异常微生物定植， 临床前IBD患者粘膜活检组织中的过表达基因。我们之前发现了一个缺陷 在DUOX 2中，导致无特异性病原体小鼠中代偿性上皮防御系统的激活， 人类群体中的功能丧失等位基因与IBD易感性增加相关。然而，在这方面， 这种遗传关联的相关机制尚不清楚。我们的目标是 确定DUOX 2功能丧失遗传变异如何使个体易受生态失调的影响， 粘膜免疫稳态的丧失导致IBD。我们假设IL-17 C的失调 信号传导是DUOX 2相关IBD的关键致病驱动因素。建议的理由 研究表明，一旦知道DUOX 2缺陷型宿主中IL-17 C信号转导的失调是如何促成 对于IBD的发病机制，可以开发新的策略来识别高危个体并恢复 体内平衡，以防止IBD的发作。我们将检验我们的假设，从而达到我们的目的 通过追求以下具体目标：1.确定DUOX 2功能丧失的机制 IL 17 C轴的微生物依赖性激活。2.评估IL 17 RE样蛋白的功能， 未表征的IBD风险因素。3.研究慢性IL-17 C活化在DUOX 2缺陷型宿主中的作用 作为IBD发病机制的驱动因素。拟议工作的预期成果是一个机械框架， DUOX 2变体如何导致IBD风险增加，即通过持续激活IL 17 C介导的 由于异常的微生物-上皮相互作用引起的免疫反应。这样的结果预计将有一个 重要的积极影响，因为了解DUOX 2变异如何有助于IBD发病机制， 极有可能为预防和治疗相关疾病提供新的目标， 失调的微生物-肠道相互作用（例如，IBD，IBS，结肠癌），除了从根本上 推进肠道粘膜免疫领域。

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.