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.

项目概要/摘要微生物和遗传易感因素之间的相互作用对于疾病的发展至关重要炎症性肠病 (IBD) 的先天机制，特别是通过模式识别受体。 (PRR) 途径是宿主对微生物反应的启动驱动因素，其中有超过 240 个与微生物相关的基因座。 IBD 中，许多基因在多个水平上调节宿主 PRR 反应，并赋予一些最大的尽管最近在 IBD 相关疾病中发现了重大发现，但在自身免疫中观察到了遗传效应。遗传学方面，大多数遗传位点的功能后果尚未确定。微生物产物激活 PRR 的结果是诱导细胞因子和微生物清除此外，IBD 的主要特征是细胞因子失调和抗微生物反应， PRR 引起的结果的个体差异会影响疾病的易感性。证实多个 IBD 相关基因的多态性导致个体间变异在 PRR 诱导的细胞因子和微生物清除途径中，我们将能够更清楚地在这种二分法的背景下对个体进行全面、有力的研究。定义由疾病相关的人类变异驱动的功能改变可以提供巨大的帮助深入了解 IBD 的核心机制；利用自然发生的人类遗传变异系统地“扰动”一个实验系统代表了一种精确的有利方法定义已建立的和新颖的 PRR 介导机制，介导细胞因子之间的平衡因此，我们将利用一个大型、功能强大的队列来筛选。 IBD 相关多态性导致 PRR 引发的细胞因子分泌和个体之间的微生物清除，然后定义分子机制，从而确定所涉及的 IBD 相关基因以及已确定的多态性可调节 PRR 诱导的结果。关联这些综合研究将深入了解那些调节 PRR 的 IBD 相关位点是否诱导细胞因子分泌和细菌清除是通过功能丧失或获得来实现的，相关基因介导其对这些 PRR 诱导结果的贡献的机制，以及通过检查单核细胞多态性对基因功能的具体影响这些全面的机制研究对于来自选定载体的细胞至关重要。未来的研究将检查基因在体内的影响，并最终改善疾病分类和治疗靶向。