Functional outcomes of inflammatory bowel disease associated variants

炎症性肠病相关变异的功能结果

基本信息

批准号：
10733023
负责人：
CLARA ABRAHAM
金额：
$ 72.67万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-18 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10733023
关键词：
Acetylmuramyl-Alanyl-Isoglutamine Autoimmunity Automobile Driving Candidate Disease Gene Cells Classification Colony-forming units Deubiquitinating Enzyme Development Disease Disease susceptibility Endoplasmic Reticulum Equilibrium Future Genes Genetic Genetic Diseases Genetic Polymorphism Genetic Predisposition to Disease Genetic Variation Human Human Genetics Immune Immune response Individual Infection Inflammatory Inflammatory Bowel Diseases Intestinal Diseases Intestines JAK2 gene MAP3K8 gene Macrophage Maps Mediating Microbe Molecular Outcome Pathogenesis Pathway interactions Patients Pattern Recognition Pattern recognition receptor Predisposition Proteins Quantitative Trait Loci Reactive Nitrogen Species Reactive Oxygen Species Receptor Activation Role STAT1 gene STAT3 gene STAT4 gene Single Nucleotide Polymorphism Stat5 protein System TNFSF15 gene Testing Tissues Toll-like receptors Ulcerative Colitis Variant antimicrobial autocrine cohort cytokine density disease classification functional outcomes gain of function gene function genomic locus human disease improved in vivo insight inter-individual variation knock-down microbial microbial disease microbial products monocyte new therapeutic target novel novel therapeutics paracrine receptor response risk variant therapeutic target ubiquitin isopeptidase

项目摘要

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 >240 loci associated to IBD, a number of genes modulate host PRR responses at many levels and confer some of the largest genetic effects observed in autoimmunity. Despite the significant recent discoveries in IBD-associated genetics, the functional consequences of the majority of the genetic loci have yet to be identified. A central outcome of PRR activation by microbial products is induction of cytokine and microbial clearance pathways. Further, IBD is largely characterized by dysregulated cytokines and anti-microbial responses, and the inter-individual variation in PRR-induced outcomes influences the disease susceptibility. We hypothesize that polymorphisms in multiple IBD-associated genes contribute to inter-individual variation in PRR-induced cytokine and microbial clearance pathways, and that we will be able to more clearly classify individuals in the context of this dichotomy. 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 mediating the balance between 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 and microbial clearance across individuals and then define the molecular mechanisms wherein the implicated IBD-associated genes, as well as the identified polymorphisms, regulate PRR-induced outcomes. Relevance These combined studies will provide insight into whether those IBD-associated loci that regulate PRR- induced 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, for improved disease classification and therapeutic targeting.

项目摘要/摘要微生物和遗传敏感性因素之间的相互作用对于发展炎症性肠病（IBD）。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的启动驱动因素。 > 240本地关联 IBD，许多基因在许多层面上调节宿主PRR响应，并会议一些最大的基因在自身免疫性中观察到的遗传效应。尽管在IBD相关的最新发现中有很大的发现遗传学，大多数遗传基因座的功能后果尚未确定。中央微生物产物激活PRR的结果是诱导细胞因子和微生物清除率途径。此外，IBD的特征在很大程度上是细胞因子和抗微生物反应的失调， PRR诱导的结局的个体差异会影响疾病的敏感性。我们假设多种IBD相关基因中的多态性有助于个体差异在PRR诱导的细胞因子和微生物清除途径中，我们将能够更清楚在这种二分法的背景下对个体进行分类。全面的系统性研究定义由疾病相关的人类变异驱动的功能变化可以提供巨大的深入了解IBD的中心机制；利用自然存在的人类遗传变异系统地“干扰”实验系统代表了精确的一种有利的方法定义已建立的新型PRR介导的机制，介导细胞因子之间的平衡分泌和微生物清除。因此，我们将利用一个大型，有力的队列进行筛选 IBD相关的多态性导致PRR引起的细胞因子分泌的变化和跨个体的微生物清除率，然后定义分子机制，其中所暗示 IBD相关的基因以及所鉴定的多态性调节PRR诱导的结果。关联这些合并的研究将提供有关调节PRR-的IBD相关基因座的洞察力诱导的细胞因子分泌和根本清除通过损失或功能获得实施基因介导其对这些PRR诱导的结果的贡献的机制，以及多态性对基因功能的具体后果，通过检查单核细胞来自选定载体的细胞。这些全面和机械研究对于未来的研究将在体内和最终检查基因后果，以改善疾病分类和治疗靶向。