Secondhand smoke and asthma: Mechanistic outcomes of DNA methylation in T cells

二手烟与哮喘：T 细胞 DNA 甲基化的机制结果

• 批准号: 8791343
• 负责人: RACHEL L MILLER
• 金额: $ 56.85万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-15 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8791343
• 关键词: Adult; Affect; Air Pollutants; Area; Asthma; Biological Markers; Boxing; Cell physiology; Cells; Child; Childhood; Chronic Disease; Clinical; DNA; DNA Methylation; Disease; Environmental Exposure; Environmental Policy; Environmental Risk Factor; Environmental Tobacco Smoke; Epigenetic Process; Eragrostis; Event; Exposure to; Functional disorder; Gene Expression; Genes; Genetic; Health; Hospitalization; Inflammation; Institutes; Interferons; Interleukin-10; Interleukin-4; Link; Measures; Mediating; Methylation; Molecular; Monozygotic Twinning; Monozygotic twins; Outcome; Pathogenesis; Pathology; Patients; Phenotype; Principal Investigator; RNA; Regulatory T-Lymphocyte; Research; Research Design; Risk Management; Site; Smoke; Smoking; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic Intervention; Time; Twin Multiple Birth; asthmatic; cohort; early childhood; environmental tobacco smoke exposure; improved; in utero; innovation; lifetime risk; methylation pattern; novel; novel strategies; peripheral blood; prevent; programs; promoter; respiratory; response; screening

DESCRIPTION (provided by applicant): Exposure to secondhand smoke (SHS) is associated with a greater lifetime risk of developing asthma, more severe asthma, and increased asthma hospitalizations for both children and adults. While much of the immunopathogenesis of asthma remains incompletely understood, key molecular events include changes in regulatory T cell (Treg) and effector T cell (Teff) activity in response to exposure to several air pollutants including SHS. Previous results from the Nadeau and Miller research groups suggest that Treg and Teff are epigenetically regulated, and their alterations affect the expression of several asthma genes and asthma- related clinical outcomes. While exposure to SHS has been shown to induce epigenetic alterations, and epigenetic changes in asthma genes may be associated with asthma, causal relationships have not been demonstrated. This proposal will try to establish a novel approach of SHS research by determining relationships between SHS exposure and asthma using uniquely linked mechanistic studies and an innovative study design. Key to this proposal is the intent to conduct studies in a well-phenotyped monozygotic twin (MZT) cohort including cases discordant on exposure to SHS and asthma that can determine the association of SHS-induced epigenetic marks, and the timing of this association, on asthma in the absence of differences in genetic backgrounds and in utero and early childhood environmental exposures, methodological limitations from prior studies. We hypothesize that exposure to SHS is associated with current asthma in adults, and this association is mediated through DNA methylation of asthma genes in Treg and Teff cells and the consequential downstream cellular events. Specifically, to understand the mechanisms of SHS-induced pathology in asthma and inflammation, we propose to: Aim 1: Test whether CpG methylation levels of specific genetic loci are altered in MZT discordant for smoking and asthma. Aim 2. Determine if minimization of exposure to SHS is associated with a decrease in methylation of Foxp3, IL-10, in Treg, and IFN? in Teff and an increase in methylation of IL-4 in Teff over time. Aim 3. Determine how methylation levels of Foxp3, IL-10, IFN?, IL-4 are influenced by never, prior (only in utero or only childhood), or current SHS exposure in asthmatic and nonasthmatic twins by estimating main effects and interactions and controlling for period of asthma onset. If the aims are achieved, this proposal should improve our understanding of the mechanisms by which exposure to SHS contributes to asthma and identify novel biomarker of smoke-related airway disease so that environmental policy and risk management can be developed more effectively, and screening and/or therapeutic interventions may be instituted earlier. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

描述（由申请人提供）：接触二手烟（SHS）与儿童和成人终生患哮喘、更严重哮喘的风险增加以及哮喘住院率增加相关。虽然哮喘的大部分免疫发病机制仍不完全清楚，但关键的分子事件包括调节性 T 细胞 (Treg) 和效应 T 细胞 (Teff) 活性因暴露于包括二手烟在内的几种空气污染物而发生的变化。 Nadeau 和 Miller 研究小组之前的结果表明，Treg 和 Teff 受到表观遗传调控，它们的改变会影响多种哮喘基因的表达和哮喘相关的临床结果。虽然暴露于二手烟已被证明会引起表观遗传改变，并且哮喘基因的表观遗传变化可能与哮喘相关，但因果关系尚未得到证实。该提案将尝试通过使用独特的相关机制研究和创新的研究设计来确定二手烟暴露与哮喘之间的关系，从而建立二手烟研究的新方法。该提案的关键是打算在表型良好的同卵双胞胎 (MZT) 队列中进行研究，包括暴露于二手烟和哮喘的病例，这些病例可以确定二手烟引起的表观遗传标记的关联，以及这种关联的时间，哮喘在遗传背景、子宫内和幼儿期环境暴露不存在差异的情况下，以及先前研究的方法学局限性。我们假设接触二手烟与成人目前的哮喘有关，这种关联是通过 Treg 和 Teff 细胞中哮喘基因的 DNA 甲基化以及随之而来的下游细胞事件介导的。具体来说，为了了解 SHS 诱导的哮喘和炎症病理机制，我们建议： 目标 1：测试吸烟和哮喘不一致的 MZT 中特定基因位点的 CpG 甲基化水平是否发生改变。目标 2. 确定尽量减少 SHS 暴露是否与 Treg 中的 Foxp3、IL-10 和 IFN 甲基化减少有关？ Teff 中的 IL-4 甲基化随着时间的推移而增加。目标 3. 通过估计主效应和相互作用，确定哮喘和非哮喘双胞胎中从来没有、之前（仅在子宫内或仅在儿童期）或当前的 SHS 暴露如何影响 Foxp3、IL-10、IFN?、IL-4 的甲基化水平并控制哮喘发作的时间。如果目标实现，该提案应提高我们对接触二手烟导致哮喘的机制的理解，并确定与烟雾相关的气道疾病的新生物标志物，以便更有效地制定环境政策和风险管理，并进行筛查和/或或者可以更早开始治疗干预。 PHS 398/2590（修订版 06/09） 页面延续 格式页面