Genomics of NFκB-mediated gene regulation in multiple sclerosis

多发性硬化症中 NFκB 介导的基因调控的基因组学

• 批准号: 9761429
• 负责人: Chris Cotsapas
• 金额: $ 72.96万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761429
• 关键词: Acetylation; Active Sites; Address; Affect; Alleles; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Automobile Driving; Binding; Binding Sites; Biological; Biological Models; Biological Process; CD4 Positive T Lymphocytes; Cell Proliferation; Cell Survival; Cell physiology; Cells; Central Nervous System Diseases; Collaborations; Cues; Cytokine Signaling; Data; Development; Disease; Dissection; Early Diagnosis; Enhancers; Event; Exhibits; Experimental Autoimmune Encephalomyelitis; Family; Flow Cytometry; Fumarates; Functional disorder; Gene Activation; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Enhancer Element; Genetic Load; Genetic Predisposition to Disease; Genome; Genomic Segment; Genomic approach; Genomics; Hair; Haplotypes; Heritability; Histones; Human; Immune; Immune response; Immunosuppression; Individual; Infection; Inflammation; Lead; Lysine; Maps; Measures; Mediating; Mediator of activation protein; Molecular; Multiple Sclerosis; Natural Immunity; Nuclear; Nucleic Acid Regulatory Sequences; Onset of illness; Pathogenesis; Pathway interactions; Phenotype; Phosphorylation; Predisposition; Production; Regulation; Regulator Genes; Regulatory Element; Risk; Role; Signal Transduction; Stimulus; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Tertiary Protein Structure; Testing; Therapeutic Agents; Variant; adaptive immunity; autoreactive T cell; autoreactivity; biomarker development; cell type; chromatin immunoprecipitation; cytokine; disorder risk; experimental study; falls; genetic variant; genome wide association study; genome-wide; innovation; mRNA sequencing; mouse model; multiple sclerosis patient; nervous system disorder; novel therapeutics; programs; response; risk variant; tool; transcription factor; transcriptome sequencing; white matter

Abstract Multiple sclerosis (MS) is a potentially progressive, autoimmune neurological disorder of the central nervous system (CNS) white matter presumably mediated by autoreactive CD4+ T cells. The disease is a consequence of both genetic predisposition and environmental triggers. Recent genome-wide association studies (GWAS) have identified over 100 genetic variants associated with increased risk of developing MS. Many of these variants fall in a limited number of signaling cascades primarily associated with immune responses and cytokine signaling, which suggests they are key biological nodes where genetic and environmental cues interact to predispose an individual towards autoimmunity, prior to the onset of disease. However, the functional mechanisms by which these variants impact immune responses, and ultimately lead to the development of MS, are largely unknown. Understanding the disease risk state mediated by these variants would allow us to determine both the pathogenesis of MS and also identify individuals – irrespective of genetic load – who exhibit it and are consequently at risk. Thus, uncovering this state has implications both for early diagnosis and the development of biomarkers and new therapeutic agents. NFκB is a master regulator of both innate and adaptive immunity, and is critical for activation, proliferation, differentiation, and cytokine production in multiple immune cell types, including the CD4+ T cells critical to MS pathogenesis. GWAS studies have identified NFκB as a central pathway in susceptibility to multiple autoimmune conditions including MS, and several strands of evidence support its causal role: MS patients exhibit higher NFκB signaling than controls; many GWAS risk variants affect NFκB signaling; and several MS disease-modifying agents inhibit this pathway. It is therefore an excellent model system to explore genetically mediated alterations in signaling cascades associated with disease. Here, we propose a systematic dissection of how alterations in NFκB signaling lead to altered gene regulatory programs and CD4+ T cell function, as an archetype of a disease-causing pathway inducing a risk state. To do so we will (i) establish how MS genetic variants alter stimulus-dependent NFκB signaling in CD4+ T cells alter gene regulation; and (ii) determine how MS risk variants in NFkB binding sites affect regulation of target genes. We will use an innovative, integrated genome-wide genomic approach simultaneously assessing NFκB signaling, its binding to and concomitant activation of cis-regulatory regions and resulting gene expression. Thus we will develop an experimental paradigm to comprehensively examine how risk variants affecting gene regulation lead to autoimmune disease risk. These studies represent significant innovation, as they take an integrative, unbiased approach to the problem of understanding how changes to NFκB-mediated signaling result in alterations to gene regulatory programs and subsequent differences CD4+ T cell phenotype.

摘要 多发性硬化症(MS)是一种潜在的进行性、自身免疫性中枢神经系统疾病 中枢神经系统(CNS)白质可能由自身反应性的CD4+T细胞介导。这种疾病是一种后果 既有遗传倾向也有环境诱因。最新全基因组关联研究(GWAS) 已经确定了100多个与多发性硬化症发病风险增加有关的基因变异，其中许多 变异体落在有限数量的信号级联中，主要与免疫反应和 细胞因子信号传递，这表明它们是遗传和环境线索的关键生物节点 在疾病发作之前，相互作用使个人容易产生自身免疫。然而， 这些变异影响免疫反应的功能机制，最终导致 多发性硬化症的发展，在很大程度上是未知的。了解由这些变异体介导的疾病风险状态 将使我们能够确定多发性硬化症的发病机制，并识别个体--而不考虑遗传因素 负载-谁展示了它，因此处于危险之中。因此，发现这种状态对早期 生物标志物和新的治疗药物的诊断和开发。 核因子κB是天然免疫和获得性免疫的主要调节者，对激活、增殖、 多种免疫细胞类型的分化和细胞因子的产生，包括对MS至关重要的CD4+T细胞 发病机制。GWAS研究发现，NFκB是多发性骨髓瘤易感性的中心途径 包括多发性硬化症在内的自身免疫状况和几条证据支持其因果作用：多发性硬化症患者 表现出比对照组更高的NFκB信号；许多GWA风险变种影响NFκB信号；以及几个MS 疾病修饰剂抑制了这一途径。因此，这是一个值得探索的极好的模型系统 与疾病相关的信号级联中的基因介导的改变。在这里，我们提出一种 系统剖析核因子κB信号改变如何导致基因调控程序改变和 CD4+T细胞的功能，作为一种诱发危险状态的致病途径的原型。 为此，我们将(I)建立MS基因变异如何改变CD_4+T细胞中依赖刺激的NF-κB信号 改变基因调控；以及(Ii)确定NFkB结合位点上的MS风险变异如何影响对 靶基因。我们将使用一种创新的、整合的全基因组方法同时评估 核因子κB信号、其与顺式调控区的结合和伴随的激活以及由此产生的基因 表情。因此，我们将开发一个实验范式来全面检查风险变量 影响基因调控会导致自身免疫性疾病的风险。这些研究代表着重大的创新，因为 他们采取综合的、不偏不倚的方法来理解NFκB如何改变的问题 信号转导导致基因调控程序的改变和随后的CD4+T细胞表型的差异。