Chronic outdoor air pollution, airway epithelial "omics" and asthma exacerbations in children

摘要： 室外空气污染是儿童哮喘恶化的一个已知原因，但在日常工作中很少得到解决 哮喘护理。必须解决科学知识与临床实践之间的差距，以改善 哮喘儿童的保健。虽然没有“安全”的污染水平，但个人对这两种空气的敏感性 儿童的污染和哮喘恶化情况各不相同。儿童哮喘发作很难预测， 导致缺课和缺课，并大大增加医疗保健利用率和成本。它 目前还不清楚我们目前的哮喘疗法是否可以预防污染引起的哮喘恶化。减少污染 政策是最好的干预措施，但在保证所有人享有“清洁”空气之前，开发生物标记物 需要确定最有可能因污染而病情加重的儿童，以制定干预措施。 气道上皮是研究组学和开发污染引起的新生物标志物的理想组织 哮喘恶化，因为哮喘易感基因在气道上皮和污染物中表达 （例如颗粒物 <2.5𝜇m (PM2.5)）会引起表观遗传和基因表达变化。鲜为人知的是 慢性污染暴露对哮喘儿童 DNA 甲基化和基因表达的影响，或 这些变化是否与哮喘恶化有关。此外，尚不清楚是否可以避免污染 建议（空气质量指数 (AQI)）会导致 DNA 甲基化或基因表达差异。这个 该提案将： 1) 确定 PM2.5 暴露与住宅靠近主要道路之间的关联 （与交通相关的空气污染的代表）和（a）全基因组 DNA 甲基化和（b）基因表达 来自哮喘儿童的鼻（气道）上皮； 2) 识别差异DNA甲基化标记或 与哮喘恶化相关的表达基因（根据 PM2.5 或道路暴露水平）；和 3) 进行探索性分析以估计环境保护局资助的影响 来自哮喘儿童试验的 AQI 对 DNA 甲基化和基因表达的行为干预。目标 1-2 使用两项已完成的 NIH 资助研究的现有数据。目标 3 使用飞行员储存的生物样本 对接受哮喘行动计划（即临床护理）AQI 干预的儿童进行的随机临床试验。 该提案解决了一个未满足的需求，即开发污染物诱发哮喘的“组学”标记 儿童病情加重。 Rosser 博士的职业发展计划提供了对统计基因组学的掌握 方法和分析，并建立在临床试验管理和分析技能的基础上。她处于有利位置 她提出的研究给出了流行病学背景、空间建模技能和试点数据。这个职业 开发奖将为 R01 提供技能和初步数据，以测试是否 表观遗传/基因标记可预测哮喘结果的风险以及对 AQI 干预的反应。

ABSTRACT: Outdoor air pollution is a known cause of childhood asthma exacerbations yet is rarely addressed in routine asthma care. This gap between scientific knowledge and clinical practice must be addressed to improve healthcare for children with asthma. While there is no ‘safe’ level of pollution, personal susceptibility to both air pollution and asthma exacerbations varies in children. Childhood asthma exacerbations are difficult to predict, lead to missed school and parental work days, and contribute substantially to healthcare utilization and costs. It is unclear if our current asthma therapies protect against pollution-induced exacerbations. Pollution reduction policies are the best intervention, yet until such time as ‘clean’ air is guaranteed for all, developing biomarkers identifying children at greatest risk of pollution-induced exacerbations are needed to develop interventions. The airway epithelium is an ideal tissue to study omics and develop new biomarkers of pollution-induced asthma exacerbations, as susceptibility genes for asthma are expressed in airway epithelium and pollutants (e.g. particulate matter <2.5𝜇m (PM2.5)) induce epigenetic and gene expression changes. Little is known about the effects of chronic pollution exposure on DNA methylation and gene expression in children with asthma, or whether such changes are associated with asthma exacerbations. Further, it is unknown if pollution avoidance recommendations (the Air Quality Index (AQI)) results in differential DNA methylation or gene expression. This proposal will: 1) determine the association between exposure to PM2.5 and residential proximity to a major road (a proxy for traffic-related air pollution) and (a) genome-wide DNA methylation and (b) gene expression in nasal (airway) epithelium from children with asthma; 2) identify differentially DNA methylated markers or expressed genes (by exposure level to PM2.5 or roadway) that are associated with asthma exacerbations; and 3) conduct an exploratory analysis to estimate the effects of the Environmental Protection Agency-sponsored AQI behavioral intervention on DNA methylation and gene expression from a trial of children with asthma. Aims 1- 2 uses existing data from two completed NIH-funded studies. Aim 3 uses banked biospecimens from a pilot randomized clinical trial of children receiving the AQI intervention on asthma action plans (i.e. clinical care). This proposal addresses an unmet need, namely developing ‘omic’ markers of pollutant-induced asthma exacerbations in children. Dr. Rosser’s career development plan provides for mastery of statistical genomic methods and analyses, and builds upon clinical trial management and analysis skills. She is well positioned for her proposed research given epidemiology background, skills with spatial modeling, and pilot data. This career development award will provide the skills and preliminary data for an R01 seeking to test whether epigenetic/gene markers predict risk of asthma outcomes and response to the AQI intervention.