Mitochondrial DNA biomarkers to assess responses to changes in personal environmental exposures in pediatric urban asthma

城市儿童不成比例地暴露在空气污染和引发哮喘的室内过敏原中 症状。为了更好地解决这个公共卫生问题，我们建议利用两个既定的和 可比较的城市队列：1)随机对照试验(RCT)：将环境控制作为附加疗法 儿童哮喘“(ECATCH)，正在确定单独定制、多方面添加的疗效 6个月以上家庭环境控制策略(ECS)至控制剂药物(Medicy)滴定 主要是患有持续性哮喘的非裔美国儿童，以及2)观察性病例对照 非洲裔美国人和多米尼加人6个月的相关空气污染哮喘研究 患有和不患有哮喘的儿童。我们建议确定新的线粒体(Mt)DNA的贡献 捕捉对多种环境应激源的反应的生物标志物，并且对动态更敏感 对肺功能和呼吸道炎症的影响。我们的目标是阐明这种动态的相互作用 在城市多种炎症性暴露的减少之间，线粒体DNA含量的可归因性变化 线粒体调节基因的甲基化，以及随着时间的推移哮喘结果的改善。分成两份 定义明确的代表城市儿童少数群体的队列，我们假设 个体化ECS和其他时间相关改变后的线粒体损伤 环境暴露与肺功能和呼吸道炎症的改善有关。我们 预测不同个人环境变化后的中间线粒体生物标志物 暴露可能与临床结果直接相关。使用两种重复测量口腔线粒体DNA含量和 置换环和其他对线粒体功能重要的区域的口腔基因组DNA甲基化， 我们建议：1)确定ECATCH哮喘患者、TAPAS患者线粒体生物标志物的差异 哮喘患者和非哮喘对照人群，以及线粒体生物标记物与 同时测量哮喘患者呼出的一氧化氮(ENO)和肺功能 六个月。2)确定重复线粒体生物标记物与重复驻留措施的相关性 细颗粒物(PM)2.5和其他致哮喘暴露，以及3)探索6个月的治疗 个性化多层面ECS加中药与单纯中药(即ECATCH RCT小组分配) 持续性哮喘患者会改变线粒体生物标志物。来自这两个群体的重大关联将 在我们的单面环境干预RCT中复制：小鼠过敏原和哮喘干预 审判“(Maait)。这项提议旨在捕捉到新的线粒体生物标记物在测量 氧化损伤诱导和修复后的动态生物反应，由一个 孩子不断变化的个人环境。这些结果可能会指导更有效的个性化生物标志物- 对患有持续性哮喘的城市儿童的指导治疗。

Urban children are exposed disproportionately to air pollution and indoor allergens that trigger asthma symptoms. To better address this public health problem, we propose to leverage two established and comparable urban cohorts: 1) randomized controlled trial (RCT) “Environmental Control as Add-on Therapy in Childhood Asthma” (ECATCh) that is determining the efficacy of adding individually tailored, multi-faceted home environmental control strategy (ECS) to titration of controller medication (TCM) over 6 months among predominantly African American children with persistent asthma, and 2) observational case control “Traffic Associated Air Pollution Asthma Study” (TAPAS) over 6 months among African American and Dominican children with and without asthma. We propose to determine the contribution of novel mitochondrial (mt) DNA biomarkers that capture responses to multiple environmental stressors, and are more sensitive to the dynamics of dysregulation, on lung function and airway inflammation. Our objective is to elucidate the dynamic interplay between reductions in multiple inflammatory urban exposures, attributable changes in mtDNA content and methylation of mitochondrial regulatory genes, and improvements in asthma outcomes over time. In two well-defined cohorts representing minority urban pediatric populations, we hypothesize that reversal of mitochondrial damage following personalized ECS and other time-related changes in multiple environmental exposures is associated with improved lung function and airway inflammation. We predict that intermediate mitochondrial biomarkers following changes in diverse personal environmental exposures may link directly to clinical outcomes. Using two repeat measures of buccal mtDNA content and buccal genomic DNA methylation of displacement loop and other regions important to mitochondrial function, we propose to: 1) Determine differences in mitochondrial biomarkers among ECATCh asthma cases, TAPAS asthma cases, and TAPAS nonasthmatic controls, and the associations of mitochondrial biomarkers with exhaled nitric oxide (eNO) and lung function within asthma cases, measured concurrently and as changes over 6 months. 2) Determine associations of repeat mitochondrial biomarkers with repeat residential measures of fine particulate matter (PM)2.5 and other asthmogenic exposures, and 3) Explore whether 6-month treatment with personalized multi-faceted ECS plus TCM vs TCM alone (i.e. ECATCh RCT group assignment) of persistent asthmatics changes mitochondrial biomarkers. Significant associations from these two cohorts will be replicated in our single-faceted environmental intervention RCT “Mouse Allergen and Asthma Intervention Trial” (MAAIT). This proposal intends to capture the pivotal role of novel mitochondrial biomarkers in measuring the dynamic biological responses following induction and remediation of oxidative damage, triggered by a child’s changing personal environment. These results could direct more effective personalized biomarker- guided therapy for urban children with persistent asthma.