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

计划总监/首席研究员（最后，第一，中间）：卡里·纳多（Nadeau）；米勒，雷切尔·L。 项目摘要（摘要） 接触二手烟（SHS）与患哮喘的终身风险更大，更多 严重的哮喘，儿童和成人的哮喘住院增加。虽然大部分 哮喘的免疫致病发生仍然不完全理解，关键分子事件包括变化 调节性T细胞（Treg）和效应T细胞（TEFF）活性，以响应几种空气污染物 包括shs。 Nadeau和Miller研究小组的先前结果表明Treg和Teff是 表观遗传调节，它们的改变会影响几种哮喘基因和哮喘的表达 相关的临床结果。虽然已经显示出暴露于SHS会诱导表观遗传改变，而 哮喘基因的表观遗传变化可能与哮喘有关，因果关系尚未是 证明。该建议将通过确定来建立SHS研究的新方法 使用独特的机械研究和创新的SHS暴露与哮喘之间的关系 研究设计。该提案的关键是意图在良好的单卵双胞胎中进行研究 （MZT）队列，包括暴露于SHS和哮喘的病例，可以确定该关联 在没有差异的情况下，SHS诱导的表观遗传标记和该关联的时间 在遗传背景，子宫和幼儿期环境暴露中，方法论上的局限性 从先前的研究。我们假设暴露于SHS与成人当前的哮喘有关，这 通过Treg和Teff细胞中哮喘基因的DNA甲基化以及 结果下游细胞事件。具体而言，要了解SHS诱导的机制 哮喘和炎症中的病理学，我们建议： AIM 1：测试MZT不一致的特定遗传局部甲基化水平是否改变了吸烟 和哮喘。 AIM 2。确定最小化SHS的暴露是否与Foxp3的甲基化降低有关 IL-10，在Treg和Teff中的IFN`以及TEFF随时间的IL-4的甲基化增加。 目标3。确定FOXP3，IL-10，IFNTH，IL-4的甲基化水平如何受到先验的影响（仅在 子宫或唯一的童年），或通过估计主要的哮喘和非心血管双胞胎中的当前SHS暴露 影响和相互作用以及控制哮喘发作期。 如果实现了目标，则该提议应提高我们对所采用机制的理解 暴露于SHS会导致哮喘，并确定与烟有关气道疾病的新型生物标志物，以便 可以更有效地制定环境政策和风险管理，并进行筛查和/或 治疗干预措施可能会较早进行。 PHS 398/2590（修订版06/09）页面延续格式页面