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.

抽象的 多发性硬化症（MS）是一种潜在的进行性的自身免疫性神经系统疾病 系统（CNS）的白质大概是由自动反应性CD4+ T细胞介导的。这种疾病是结果 遗传易感性和环境触发因素。最近全基因组关联研究（GWAS） 已经确定了与增加MS的风险增加有关的100多种遗传变异。其中许多 变体属于有限数量的信号级联，主要与免疫调查有关 细胞因子信号传导，这表明它们是遗传和环境提示的关键生物淋巴结 在疾病发作之前，相互作用以使人倾向于自身免疫性。但是， 这些变体影响免疫反应并最终导致的功能机制 MS的发展在很大程度上未知。了解这些变体介导的疾病风险状态 将使我们能够确定MS的发病机理，也可以识别个体 - 无论仿制药 负载 - 暴露了它，因此处于危险之中。那是对这种状态的含义，对早期有影响 诊断和生物标志物和新治疗剂的发展。 NFκB是先天和适应性免疫组织化学的主要调节剂，对于激活，增殖至关重要 在多种免疫球类型中的分化和细胞因子产生，包括对MS至关重要的CD4+ T细胞 发病。 GWAS研究已将NFκB确定为易感性的中心途径 自身免疫性条件在内 暴露于比对照的更高的NFκB信号传导；许多GWAS风险变体会影响NFκB信号传导；和几个MS 疾病改良剂抑制了这一途径。因此，它是一个探索的绝佳模型系统 遗传介导的与疾病相关的信号级联反应的改变。在这里，我们建议 系统解剖NFκB信号传导中的变化如何导致基因调节程序的改变和 CD4+ T细胞功能，作为引起疾病途径的原型诱导风险状态。 为此，我们将（i）确定MS遗传变异如何改变CD4+ T细胞中刺激依赖性NFκB信号传导 改变基因调节； （ii）确定NFKB结合位点中的MS风险变体如何影响调节 靶基因。我们将使用简单地评估全基因组基因组方法的创新，全基因组的基因组方法 NFκB信号传导，其与顺式调节区域的结合和伴随的激活和结果基因 表达。我们将开发一个实验范式，以全面研究风险变体 影响基因调节会导致自身免疫性疾病风险。这些研究代表了重大创新，如 他们采用一种综合的，公正的方法来理解如何变化NFκB介导的 信号导致基因调节程序的改变和随后的差异CD4+ T细胞表型。