Epigenomics of T cells and innate immune cells in human asthma

人类哮喘中 T 细胞和先天免疫细胞的表观基因组学

• 批准号: 8882532
• 负责人: Bjoern Peters
• 金额: $ 109.79万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-23 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8882532
• 关键词: Address; Adopted; Affect; Aging; Allergic; Allergic Disease; American; Asthma; Basophils; Biopsy; Blood; Blood Cells; Boxing; CD4 Positive T Lymphocytes; Cell Count; Cell Lineage; Cell physiology; Cells; Chromatin; Chronic; Clinical; Clinical Data; Country; Cytosine; DNA; DNA Methylation; Data; Data Set; Databases; Development; Diagnosis; Disease; Enzymes; Epigenetic Process; Extrinsic asthma; Genes; Genetic; Genetic Variation; Genome; Goals; Health; Helper-Inducer T-Lymphocyte; Histones; Human; Hydroxylation; IL13 gene; IL4 gene; IL5 gene; Immune; Immunology; Individual; Laboratories; Link; Lung Lavage Fluid; Lysine; Malignant Neoplasms; Maps; Mediating; Methods; Methylation; Modification; Molecular; Mus; Output; Pathogenesis; Patients; Pattern; Pharmaceutical Preparations; Polymorphism Analysis; Population; Proteins; RNA; RNA Sequences; Reading; Research; Role; Seminal; Severities; Severity of illness; Single Nucleotide Polymorphism; Sorting - Cell Movement; Stem cells; Symptoms; T-Lymphocyte; Testing; Tetanus Helper Peptide; Time; Work; Writing; airway inflammation; asthmatic; asthmatic patient; base; cell type; cohort; cytokine; database design; disease phenotype; epigenetic marker; epigenetic profiling; epigenome; epigenomics; genome wide association study; genome-wide; genome-wide analysis; histone modification; human disease; innovation; macrophage; methylation pattern; new therapeutic target; novel; research clinical testing; response; transcription factor; transcriptome sequencing

PROJECT SUMMARY or ABSTRACT In this multi-PI proposal we will investigate the role of epigenetic mechanisms in the pathogenesis of allergic asthma. Asthma affects 1 in 15 Americans -- over 23 million people -- thus making it one of the country's most common and also costly diseases. Current therapies do not cure asthma or control daily symptoms for patients with severe disease, prompting us to adopt "out-of-box" approaches to find novel therapies for asthma. Our goal is to directly address the unmet need for asthma sufferers by harnessing the seminal discoveries made in the field of epigenetics to benefit asthma research. Multiple lines of evidence suggest an important role for epigenetic mechanisms in asthma. Specifically, we have identified disease-specific epigenetic signatures in the T helper 2 (Th2) cytokine locus (encompassing the IL4, IL5 and IL13 genes) in patients with moderate asthma compared to patients with mild asthma or controls. In addition, we recently discovered TET proteins that convert 5-methylcytosine (5mC) to 5-hydroxymethyl-cytosine (hmC) in DNA, thus creating a completely new epigenetic mark; and have shown that Tet proteins and 5hmC are expressed in T cells. These are exciting findings because hydroxylation of 5mC alters DNA methylation status in a hitherto unprecedented way, and because DNA methylation is relevant to several fields including mammalian development, cancer, aging, cell lineage specification, genome defense, stem cell function and immunology. We propose to extend these studies genome-wide to identify epigenomic signatures that correlate with asthma development and severity, by comparing histone modifications and DNA methylation/ hydroxy- methylation patterns in enriched populations of pathogenic T cells and innate immune cells freshly isolated from blood and airways of asthmatic patients versus control individuals. Our study will be the first to define disease-related epigenetic changes in patients with well-characterized asthma, and to correlate these with disease severity to obtain specific markers for distinguishable disease states. We will test the hypothesis that asthma - a chronic allergic disease -- is characterized by perturbations in these epigenetic processes in immune cells, that can be recognized and read out as long-range epigenetic changes at relevant disease-associated loci. In Aim 1, we will map genome-wide transcriptional and histone modification patterns in immune cells that initiate and maintain airway inflammation in asthma. In Aim 2, we will profile patterns of DNA methylation and hydroxymethylation in immune cells in asthma. In Aim 3, we will identify epigenetic markers of disease by establishing and analyzing an integrated database of epigenomic, genetic, functional and clinical data. These proposed studies are novel and innovative. They will have a broad impact on our understanding of asthma, and set an important precedent for investigating the role of epigenetic mechanisms in other immune-mediated disorders. )

项目摘要或摘要 在这个多PI方案中，我们将研究表观遗传机制在变态反应发病机制中的作用 哮喘。每15个美国人中就有一个患有哮喘，超过2300万人，从而使其成为美国最大的哮喘之一 最常见也最昂贵的疾病。目前的治疗方法不能治愈哮喘或控制日常症状 严重疾病的患者，促使我们采用“开箱即用”的方法来寻找新的治疗方法 哮喘。我们的目标是通过利用精液直接解决哮喘患者未得到满足的需求 表观遗传学领域的发现有利于哮喘研究。多条证据表明 表观遗传机制在哮喘中的重要作用。具体地说，我们确定了特定于疾病的 T辅助细胞2(Th2)细胞因子基因座(包括IL4、IL5和IL13基因)的表观遗传学特征 中度哮喘患者与轻度哮喘患者或对照组比较。另外，我们最近 发现了在DNA中将5-甲基胞嘧啶(5mC)转化为5-羟甲基胞嘧啶(HMC)的Tet蛋白质， 从而创造了一个全新的表观遗传学标记；并表明Tet蛋白和5hmC是 在T细胞中表达。这些都是令人兴奋的发现，因为5mC的羟基化改变了DNA甲基化 因为DNA甲基化与几个领域相关，包括 哺乳动物发育、癌症、衰老、细胞谱系特征、基因组防御、干细胞功能和 免疫学。 我们建议将这些研究扩展到全基因组，以确定与以下因素相关的表观基因组特征 哮喘的发展和严重程度，通过比较组蛋白修饰和DNA甲基化/羟基- 新分离的致病T细胞和先天免疫细胞丰富群体的甲基化模式 哮喘患者的血液和呼吸道与对照组比较。我们的研究将第一个确定 特征明确的哮喘患者的疾病相关表观遗传学变化，以及这些变化与 疾病严重性，以获得可区分疾病状态的特定标记。 我们将测试哮喘--一种慢性过敏性疾病--的特征是 免疫细胞中的这些表观遗传过程，可以被识别并读出为远程表观遗传 相关疾病相关基因座的变化。在目标1中，我们将绘制全基因组转录和组蛋白图谱 启动和维持哮喘患者呼吸道炎症的免疫细胞的修饰模式。在目标2中，我们 将分析哮喘免疫细胞DNA甲基化和羟甲基化的模式。在《目标3》中，我们将 通过建立和分析一个完整的表观基因组数据库来识别疾病的表观遗传标记， 遗传、功能和临床数据。这些建议的研究具有新颖性和创新性。他们将会有一个 对我们对哮喘的认识产生了广泛的影响，并为研究哮喘的作用开创了重要的先例 其他免疫介导性疾病的表观遗传机制。 )