Epigenomic Origins of Overlapping Features of Asthma and COPD

哮喘和慢性阻塞性肺病重叠特征的表观基因组起源

• 批准号: 9982415
• 负责人: DAWN L DEMEO
• 金额: $ 25.92万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982415
• 关键词: Address; Adult; Age; Air Movements; Airway Disease; Asthma; Biological Markers; Childhood; Childhood Asthma; Chronic Obstructive Airway Disease; Chronic lung disease; DNA; DNA Methylation; DNA sequencing; Data; Dependence; Development; Developmental Gene; Diagnostic; Diagnostic radiologic examination; Disease; Disease Pathway; Elderly; Epigenetic Process; Epithelial Cells; Exposure to; Fetal Lung; Gene Expression; Genes; Genetic; Genetic Risk; Genetic Transcription; Genetic Variation; Growth; Human; In Vitro; Individual; Inflammatory; Life; Life Cycle Stages; Link; Lung; Lung diseases; Mediating; Mediator of activation protein; Methylation; MicroRNAs; Modeling; Molecular; Multiomic Data; Network-based; Outcome; Pathogenesis; Pathway interactions; Phenotype; Predisposition; Primary Prevention; RNA; Respiratory physiology; Risk; Risk Factors; Signal Transduction; Smoke; Smoker; Smoking; Structure of parenchyma of lung; Systems Biology; Testing; Therapeutic; Tobacco smoke; Variant; airway obstruction; airway remodeling; asthmatic; base; bronchial epithelium; cigarette smoke; cohort; differential expression; early childhood; emerging adult; epigenetic regulation; epigenetic variation; epigenomics; exome; exposure to cigarette smoke; fetal; fetal smoke exposure; genetic association; genetic variant; genome-wide; genome-wide analysis; in utero; in vitro Model; insight; knock-down; lung development; lung preservation; methylome; miRNA expression profiling; next generation sequencing; non-smoking; overexpression; preservation; response; small hairpin RNA; transcriptomics; young adult

ABSTRACT Exposure to cigarette smoke has been associated with both childhood asthma and adult COPD, and may be a key early-life environmental link impacting trajectories of fixed airflow obstruction in asthmatics and COPD. The initiation of chronic obstructive lung disease pathways and networks may occur in utero and/or during early life. The identification of common epigenetic marks between asthma and COPD and the potential fetal origins of molecular susceptibility may represent biomarkers of and/or susceptibility factors for COPD and asthma. We hypothesize that fixed airflow obstruction is associated with variability in miRNA and DNA methylation in bronchial epithelium, that genetic and epigenetic variation act together to define susceptible individuals and that a subset of genes demonstrating epigenetic perturbations in fixed airflow in asthmatics and COPD will be associated in fetal lung tissue exposed to in utero smoke, supporting common and developmental origins of fixed airflow obstruction and COPD. We propose gene-level and network-based analysis of miRNA and DNA methylation sequencing data. In Aim 1, we will use state-of-the-art next generation sequencing approaches in DNA and RNA from BE cells from 175 subjects to identify gene-specific DNA methylation and miRNA marks associated with fixed airflow obstruction in asthmatics and older smokers with COPD, followed by an assessment of significant marks in utero tobacco smoke (IUS) exposed fetal lung tissue. We will perform genome-wide analysis of bronchial epithelial (BE) cell marks from asthmatic subjects, COPD subjects, and adult smokers without lung disease. In Aim 2 we will integrate genetic and epigenetic variation to assess genetic regulation of epigenetic marks and phenotypic outcomes. We anticipate that these genetic-epigenetic signatures will identify a subset of childhood asthmatics at risk for early irreversible airflow obstruction and COPD. We will integrate methylation and miRNA signals with gene expression to assess for potential functional relevance of identified networks, and network conservation between asthma, COPD and fetal lung tissue exposed to IUS. In Aim 3, we will assess the functional features of genes identified through methylome and miRNA sequencing using in vitro gene knockdown or overexpression in BE cells, to highlight genes with a functional impact on fixed AO through airway remodeling via pro-inflammatory and pro-fibrotic mediators. In summary, this project will investigate DNA sequencing-identified methylation and miRNA marks and networks associated in asthma and COPD and replicated in fetal lung tissue to identify common pathogenesis pathways and potential fetal origins or epigenetic susceptibility. Integrating genetic, epigenetic and gene expression data may identify key overlapping pathways that influence these major smoking-related pulmonary disorders and may provide an early-life biomarker to inform primary prevention of both asthma and COPD.

抽象的 暴露于香烟烟与童年哮喘和成人COPD有关，可能是 哮喘和COPD中固定气流阻塞的轨迹的主要早期生活环境联系。这 子宫内和/或早期可能会发生慢性阻塞性肺疾病途径和网络的启动。 鉴定哮喘和COPD之间的常见表观遗传标记以及的潜在胎儿起源 分子易感性可能代表COPD和哮喘的生物标志物和/或易感因素。我们 假设固定的气流阻塞与miRNA和DNA甲基化的变化有关 支气管上皮，遗传和表观遗传学变异起来，以定义易感个体和 哮喘和COPD中固定空气中表观遗传扰动的基因部分将是 在子宫烟中暴露于胎儿肺组织，支持常见和发育起源 固定气流阻塞和COPD。我们提出了基因级和基于网络的miRNA和DNA分析 甲基化测序数据。在AIM 1中，我们将使用最新的下一代测序方法 来自175名受试者的BE细胞的DNA和RNA，以鉴定基因特异性DNA甲基化和miRNA标记 与哮喘患者中的固定气流阻塞和患有COPD的老年吸烟者有关，然后是 评估子宫烟烟（IUS）暴露的胎儿肺组织中的显着标记。我们将表演 哮喘受试者，COPD受试者和 没有肺部疾病的成年吸烟者。在AIM 2中，我们将整合遗传和表观遗传变异以评估 表观遗传标记和表型结果的遗传调节。我们预计这些遗传性景观 签名将确定童年哮喘患者的一部分，面临早期不可逆的气流阻塞和 COPD。我们将将甲基化和miRNA信号与基因表达相结合，以评估潜力 已识别网络的功能相关性以及哮喘，COPD和胎儿肺之间的网络保护 暴露于IUS的组织。在AIM 3中，我们将评估通过甲基鉴定的基因的功能特征 在BE细胞中使用体外基因敲低或过表达进行miRNA测序，以突出具有A的基因 通过促炎和促纤维化介体通过气道重塑对固定AO的功能影响。在 摘要，该项目将研究DNA测序鉴定的甲基化和miRNA标记和网络 与哮喘和COPD相关，并在胎儿肺组织中复制以鉴定常见的发病途径 以及潜在的胎儿起源或表观遗传敏感性。整合遗传，表观遗传和基因表达数据 可能会确定影响这些主要吸烟相关肺部疾病的关键重叠途径和 可以提供早期生物标志物，以告知主要预防哮喘和COPD。