Functional outcomes of inflammatory bowel disease associated variants

项目摘要/摘要 微生物和遗传易感因素之间的相互作用是发展的核心。 炎症性肠病。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初始驱动因素。在与之相关的200个基因座中 IBD，许多基因在多个水平上调节宿主的PRR反应，并赋予一些最大的 在自身免疫中观察到的遗传效应大小。尽管最近在IBD方面有了重大发现- 与遗传相关的基因座，这些基因座中的大多数的功能后果尚未确定。 微生物产品激活PRR的一个主要结果是诱导细胞因子和微生物 安全通道。炎症性肠病的主要特征是调节失调的细胞因子和抗微生物 细胞因子的反应和调节在IBD的治疗中起主要作用。人与人之间的差异 PRR诱导的结果影响感染易感性和 炎症性疾病。我们假设多个IBD相关基因的多态对 PRR诱导的细胞因子分泌和微生物清除途径的个体间差异。 系统、有力的研究全面定义了由疾病驱动的功能改变- 相关的人类变异可以为IBD的核心机制提供巨大的洞察力；利用 自然发生的人类基因变异，系统地“扰乱”一个实验系统 精确定义已建立的和新的PRR介导的机制的有利方法 信号、细胞因子分泌和微生物清除。因此，我们将利用一台大型的、动力强大的 筛选导致PRR启动的细胞因子变异的IBD相关基因多态的队列 然后确定涉及IBD的分子机制-- 相关基因以及已发现的多态性，调节PRR诱导的信号转导，细胞因子 分泌物和微生物清除途径。 相关性 这些联合研究将提供有关调控PRR的IBD相关基因座的洞察。 诱导的信号、细胞因子的分泌和细菌的清除都是通过功能的丧失或获得来实现的 其中涉及的基因调节它们对PRR诱导的结果的贡献的机制， 通过单核细胞检测，基因多态对基因功能的具体影响。 从选定载体派生的细胞。这些全面和机械性的研究将对 未来的研究将检查体内的基因后果，并最终在疾病的背景下 瞄准目标。

Project Summary/Abstract 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 200 loci associated to IBD, a number of genes modulate host PRR responses at many levels, and confer some of the largest genetic effect sizes observed in autoimmunity. Despite the significant recent discoveries in IBD- associated genetic loci, the functional consequences of the majority of these loci have yet to be identified. A central outcome of PRR activation by microbial products is induction of cytokines and microbial clearance pathways. IBD is largely characterized by dysregulated cytokines and anti-microbial responses, and modulation of cytokines plays a primary role in IBD treatment. Inter-individual variation in PRR-induced outcomes influences the critical 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 and microbial clearance pathways. Systematic, well-powered studies comprehensively defining the functional alterations driven by disease- associated human variation can provide enormous insight into central mechanisms of IBD; leveraging naturally occurring human genetic variation to systematically “perturb” an experimental system represents an advantageous approach for precisely defining established and novel PRR-mediated mechanisms of signaling, cytokine secretion and microbial clearance. 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 signaling, cytokine secretion, and microbial clearance pathways. Relevance These combined studies will provide insight into whether those IBD-associated loci that regulate PRR- induced signaling, cytokine secretion and bacterial clearance do so through a loss- or gain-of-function, the mechanisms wherein the implicated genes mediate their contributions to these PRR-induced outcomes, and the specific consequences of the polymorphisms on gene function through examination of monocyte- derived cells from selected carriers. These comprehensive and mechanistic studies will be crucial for future studies that will examine gene consequences in vivo and ultimately, in the context of disease targeting.