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: 9197326
• 负责人: RACHEL L MILLER
• 金额: $ 52.94万
• 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/9197326
• 关键词: Adult; Affect; Air Pollutants; Area; Asthma; Cell physiology; Cells; Child; Childhood; Chronic Disease; Clinical; Consequentialism; DNA; DNA Methylation; Diagnosis; Disease; Environmental Exposure; Environmental Policy; Environmental Risk Factor; Environmental Tobacco Smoke; Epigenetic Process; Eragrostis; Event; Exposure to; FOXP3 gene; Functional disorder; Gene Expression; Genes; Genetic; Hospitalization; Inflammation; Institutes; Interferon Type II; Interferon-alpha; Interleukin-10; Interleukin-4; Link; Measures; Mediating; Methodology; Methylation; Molecular; Monozygotic twins; Outcome; Pathogenesis; Pathology; Patients; Phenotype; 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 marker; novel strategies; peripheral blood; prevent; promoter; public health relevance; 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 IFNγ in Teff and an increase in methylation of IL-4 in Teff over time. Aim 3. Determine how methylation levels of Foxp3, IL-10, IFNγ, 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.

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有关。虽然哮喘的许多免疫发病机制仍不完全清楚，关键的分子事件包括调节性 T 细胞 (Treg) 和效应 T 细胞 (Teff) 活性的变化，以响应暴露于包括 SHS 在内的几种空气污染物。 Teff 受到表观遗传调节，其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 SHS 已被证明会诱发表观遗传改变，并且哮喘基因的表观遗传变化可能与哮喘相关，但因果关系尚未发现。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，从而建立一种新的二手烟研究方法。该提案的关键是在良好表型中进行研究。同卵双胞胎 (MZT) 队列，包括暴露于 SHS 和哮喘不一致的病例，可以确定 SHS 诱导的表观遗传标记的关联，以及这种关联的时间，在没有遗传背景差异的情况下以及子宫内和幼儿期与哮喘的关系环境暴露、先前研究的方法学局限性，我们发现暴露于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 甲基化以及随之而来的下游细胞介导的。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 MZT 中特定基因位点的 CpG 甲基化水平是否因吸烟和哮喘而发生改变。目标 2 是否最小化。暴露于 SHS 的程度与 Treg 中的 Foxp3、IL-10 和 Teff 中的 IFNγ 甲基化降低以及 Teff 中 IL-4 甲基化增加相关。目标 3. 通过估计主效应和时间，确定从未、之前（仅在子宫内或仅在儿童时期）或当前的 SHS 暴露对 Foxp3、IL-10、IFNγ、IL-4 的甲基化水平的影响。如果目标得以实现，该提案将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。可以更有效地制定环境政策和风险管理，并且可以更早地实施筛查和/或治疗干预措施。

项目成果

Detection of gut and mucosal peptides through TOMAHAQ in healthy individuals.

通过 TOMAHAQ 检测健康个体的肠道和粘膜肽。

• DOI: 10.1111/all.15698
• 发表时间: 2023
• 期刊: Allergy
• 影响因子: 12.4
• 作者: Parsons,ES;Liu,F;Kaushik,A;Lee,A;Schuetz,J;Dunham,D;Seastedt,H;Ogulur,I;Heider,A;Tan,G;Shah,A;Cao,S;Smith,E;Kost,L;Acharya,S;Prunicki,M;Rothenberg,M;Sindher,S;Leib,R;Akdis,CA;Nadeau,K;Lejeune,S
• 通讯作者: Lejeune,S