Functional outcomes of inflammatory bowel disease associated variants

炎症性肠病相关变异的功能结果

• 批准号: 8557263
• 负责人: CLARA ABRAHAM
• 金额: $ 36.21万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-18 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8557263
• 关键词: Autoimmune Process; Autoimmunity; Automobile Driving; Cells; Crohn' s disease; Dendritic Cells; Development; Disease; Equilibrium; Figs - dietary; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Human; Human Genetics; Immune response; Individual; Infection; Inflammatory; Inflammatory Bowel Diseases; Maps; Mediating; Microbe; Microbial Genetics; Molecular; Outcome; Pathway interactions; Pattern recognition receptor; Play; Predisposition; Receptor Activation; Regulation; Risk; Role; STAT3 gene; Signal Pathway; Single Nucleotide Polymorphism; System; Testing; Toll-like receptors; Transcript; Ulcerative Colitis; Variant; Viral; cohort; cytokine; density; functional outcomes; human disease; improved; innovation; insight; macrophage; monocyte; mycobacterial; new therapeutic target; novel; protein expression; public health relevance

DESCRIPTION (provided by applicant): The interplay between microbial and genetic susceptibility factors is central to the development of inflammatory bowel disease (IBD). Innate mechanisms, in particular through pattern recognition receptor (PRR) pathways, are the initiating drivers of host responses to microbes. Of the 163 loci associated to IBD, a broad range of likely genes modulate host responses to PRR at many levels, and confer some of the largest genetic effect sizes observed in autoimmunity. Despite the significant discoveries in IBD-associated polymorphisms over the past few years, the functional consequences of the vast majority of these loci have yet to be identified. A central outcome of PRR activation by bacterial and viral products is induction of cytokine secretion. To a large extent, IBD is characterized by dysregulated cytokines, and modulation of cytokines plays a primary role in IBD treatment. Inter-individual variation in PRR- induced cytokine secretion influences the balance between susceptibility to infection and inflammatory diseases. We hypothesize that polymorphisms in multiple IBD-associated genes contribute to inter-individual variation in PRR-induced cytokine secretion. Systematic, well- powered studies comprehensively defining the functional alterations driven by disease- associated human variation will provide enormous insight into central mechanisms of IBD; leveraging naturally occurring human genetic variation to systematic "perturb" an experimental system represents a highly innovative approach for precisely defining established and novel PRR-mediated mechanisms of cytokine secretion. Therefore, we will utilize a large, well- powered cohort to screen for IBD-associated polymorphisms contributing to the variation in PRR-initiated cytokine secretion across individuals, and then define the molecular mechanisms wherein the implicated IBD-associated genes, as well as the identified polymorphisms, regulate PRR-induced cytokine secretion.

描述（由申请人提供）：微生物和遗传易感因素之间的相互作用对于炎症性肠病（IBD）的发展至关重要。先天机制，特别是通过模式识别受体（PRR）途径，是宿主对微生物反应的起始驱动因素。在与 IBD 相关的 163 个基因座中，大量可能的基因在多个水平上调节宿主对 PRR 的反应，并赋予在自身免疫中观察到的一些最大的遗传效应。尽管过去几年在 IBD 相关多态性方面取得了重大发现，但绝大多数这些基因座的功能后果尚未确定。细菌和病毒产物激活 PRR 的一个主要结果是诱导细胞因子分泌。在很大程度上，IBD 的特点是细胞因子失调，而细胞因子的调节在 IBD 治疗中起着主要作用。 PRR 诱导的细胞因子分泌的个体差异影响感染和炎症性疾病易感性之间的平衡。我们假设多个 IBD 相关基因的多态性导致 PRR 诱导的细胞因子分泌的个体间差异。全面定义由疾病相关人类变异驱动的功能改变的系统性、强有力的研究将为 IBD 的中心机制提供深入的见解；利用自然发生的人类遗传变异来系统地“干扰”实验系统代表了一种高度创新的方法，用于精确定义已建立的和新颖的 PRR 介导的细胞因子分泌机制。因此，我们将利用一个大型的、功能良好的队列来筛选与 IBD 相关的多态性，这些多态性有助于个体之间 PRR 启动的细胞因子分泌的变化，然后定义其中涉及的 IBD 相关基因以及鉴定多态性，调节 PRR 诱导的细胞因子分泌。