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: 8630582
• 负责人: RACHEL L MILLER
• 金额: $ 61.18万
• 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/8630582
• 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; Pattern; 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; cigarette smoking; cohort; early childhood; improved; in utero; innovation; lifetime risk; novel; novel strategies; peripheral blood; prevent; programs; promoter; respiratory; response; screening

Program Director/Principal Investigator (Last, First, Middle): Nadeau, Kari C.; Miller, Rachel L. Project Summary (Abstract) 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

项目总监/首席研究员（最后、第一、中间）：Nadeau, Kari C.；Rachel L. 项目概要（摘要） 接触二手烟 (SHS) 与一生中罹患哮喘的风险增加相关 严重哮喘，并且儿童和成人的哮喘住院人数增加。 哮喘的免疫发病机制仍不完全清楚，关键分子事件包括 调节性 T 细胞 (Treg) 和效应 T 细胞 (Teff) 响应暴露于多种空气污染物的活动 包括 SHS 在内的 Nadeau 和 Miller 研究小组之前的研究结果表明，Treg 和 Teff 是 表观遗传调节，它们的改变影响一些哮喘基因和哮喘的表达 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有关，但因果关系尚未确定 该提案将尝试建立一种新的 SHS 研究方法，通过确定 使用独特的相关机制研究和创新方法研究二手烟暴露与哮喘之间的关系 研究设计的关键是在表型良好的同卵双胞胎中进行研究。 (MZT) 队列，包括在接触二手烟和哮喘方面不一致的病例，可以确定相关性 在没有差异的情况下，SHS 诱导的表观遗传标记以及这种关联的时间对哮喘的影响 在遗传背景以及子宫内和幼儿期环境暴露中，方法学上的局限性 根据之前的研究，我们发现接触二手烟与成人当前的哮喘有关。 这种关联是通过 Treg 和 Teff 细胞中哮喘基因的 DNA 甲基化介导的 具体来说，是为了了解 SHS 诱导的机制。 哮喘和炎症的病理学，我们建议： 目标 1：测试与吸烟不一致的 MZT 中特定基因位点的 CpG 甲基化水平是否发生改变 和哮喘。 目标 2. 确定尽量减少 SHS 暴露是否与 Foxp3 甲基化减少有关， Tregs 中的 IL-10 和 IFN¿ Teff 中的 IL-4 甲基化随着时间的推移而增加。 目标 3. 确定 Foxp3、IL-10、IFN 的甲基化水平如何, IL-4 受到从不、先验的影响（仅在 子宫内或仅童年），或通过估计主要的哮喘和非哮喘双胞胎当前的二手烟暴露 影响和相互作用以及控制哮喘发作期。 如果目标实现，该提案应该会增进我们对机制的理解 接触二手烟会导致哮喘，并确定与烟雾相关的气道疾病的新生物标志物，以便 可以更有效地制定环境政策和风险管理，并进行筛选和/或 治疗干预措施可以更早开始。 PHS 398/2590（修订版 06/09） 页面延续 格式页面