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: 8502755
• 负责人: Bjoern Peters
• 金额: $ 106.11万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8502755
• 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 patient; base; cell type; cohort; cytokine; database design; disease phenotype; epigenetic marker; epigenome; epigenomics; genome wide association study; genome-wide; histone modification; human disease; innovation; macrophage; new therapeutic target; novel; research clinical testing; response; transcription factor

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. )

项目总结或摘要 在这个多PI的建议，我们将调查的作用，表观遗传机制的发病机制过敏性 哮喘哮喘影响着15个美国人中的1个-超过2300万人-因此使其成为该国最严重的疾病之一。 最常见也最昂贵的疾病。目前的疗法不能治愈哮喘或控制日常症状， 这促使我们采用“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开创性的 表观遗传学领域的发现有助于哮喘研究。多种证据表明 表观遗传机制在哮喘中的重要作用具体地说，我们已经确定了疾病特异性 T辅助细胞2（Th 2）细胞因子基因座（包括IL 4、IL 5和IL 13基因）中的表观遗传标记， 中度哮喘患者与轻度哮喘患者或对照组相比。此外，我们最近 发现了泰特蛋白，其在DNA中将5-甲基胞嘧啶（5 mC）转化为5-羟甲基胞嘧啶（hmC）， 从而创造了一个全新的表观遗传标记;并已证明泰特蛋白和5 hmC是 在T细胞中表达。这是令人兴奋的发现，因为5 mC的羟基化改变了DNA甲基化 这是一个前所未有的状态，因为DNA甲基化与几个领域有关，包括 哺乳动物发育、癌症、衰老、细胞谱系特化、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范围，以确定与以下相关的表观基因组特征： 通过比较组蛋白修饰和DNA甲基化/羟基化， 新鲜分离的病原性T细胞和先天性免疫细胞富集群体中的甲基化模式 从哮喘患者的血液和气道与对照个体。我们的研究将首次定义 明确表征的哮喘患者的疾病相关表观遗传学变化，并将这些变化与 疾病严重程度，以获得可区分疾病状态的特异性标志物。 我们将检验这样一个假设，即哮喘--一种慢性过敏性疾病--的特征是呼吸系统的紊乱， 免疫细胞中的这些表观遗传过程，可以被识别和读出为长距离表观遗传过程， 相关疾病相关位点的变化。在目标1中，我们将绘制全基因组转录和组蛋白 在哮喘中，免疫细胞的修饰模式引发并维持气道炎症。在目标2中， 将描绘哮喘免疫细胞中DNA甲基化和羟甲基化的模式。在目标3中，我们 通过建立和分析表观基因组的综合数据库来鉴定疾病的表观遗传标记， 基因、功能和临床数据。这些研究具有新颖性和创新性。他们将有一个 广泛影响我们对哮喘的理解，并为研究哮喘的作用树立了重要的先例。 表观遗传机制在其他免疫介导的疾病。 )