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: 9277453
• 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 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9277453
• 关键词: Autoimmune Process; Autoimmunity; Automobile Driving; Cells; Crohn' s disease; Dendritic Cells; Development; Disease; Equilibrium; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Human; Human Genetics; Immune response; Individual; Infection; Inflammatory; Inflammatory Bowel Diseases; Mediating; Microbe; Microbial Genetics; Molecular; Outcome; Pathway interactions; Pattern recognition receptor; Play; Predisposition; Receptor Activation; 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; immunoregulation; improved; innovation; insight; inter-individual variation; knock-down; macrophage; monocyte; mycobacterial; new therapeutic target; novel; novel therapeutics; 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）：微生物和遗传敏感性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，尤其是通过模式识别受体（PRR）途径，是宿主对微生物反应的驱动因素。在与IBD相关的163个基因座中，广泛的可能基因在许多级别调节对PRR的反应，并赋予自身免疫性中观察到的一些最大的遗传效应大小。尽管在过去几年中，与IBD相关的多态性有重大发现，但这些基因座绝大多数的功能后果尚未得到识别。细菌和病毒产物激活PRR激活的主要结果是诱导细胞因子分泌。在很大程度上，IBD的特征是细胞因子失调，细胞因子的调节在IBD治疗中起主要作用。 PRR诱导的细胞因子分泌的个体间变化会影响感染和炎症性疾病的敏感性之间的平衡。我们假设多种IBD相关基因中的多态性有助于PRR诱导的细胞因子分泌的个体间变异。系统的，良好的研究全面定义了与疾病相关的人类变异所驱动的功能变化，将为IBD的核心机制提供巨大的见解。利用自然存在的人类遗传变异到系统的“扰动”实验系统代表了一种高度创新的方法，用于精确定义细胞因子分泌的已建立和新型PRR介导的机制。因此，我们将利用一个大型，功能齐全的队列来筛选与IBD相关的多态性的筛选，这有助于跨个体PRR启动的细胞因子分泌的变化，然后定义了与IBD相关的基因所涉及的分子机制，以及与识别的多态性的PRRRIK-PRRRIK-Indiccine Cytok-Indincine Cytok-Indincine cytigindscyscycy cytigincin cytigindscycy indscy cytigincinection。