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已知原因，但很少在日常生活中得到解决 哮喘护理。必须解决科学知识和临床实践之间的差距，以改善 哮喘儿童的医疗保健。虽然没有“安全”的污染水平，但个人对这两种空气的易感性 污染和哮喘的恶化在儿童中是不同的。儿童哮喘的恶化很难预测， 导致旷课和父母工作日，并大大增加了医疗保健的利用率和成本。它 目前尚不清楚我们目前的哮喘疗法是否可以预防污染导致的病情恶化。减少污染 政策是最好的干预措施，但在开发生物标志物之前，清洁的空气对所有人都是有保障的 为了制定干预措施，需要找出污染导致病情恶化风险最大的儿童。 呼吸道上皮细胞是研究组学和开发新的污染生物标志物的理想组织 哮喘加重，因为哮喘易感基因在呼吸道上皮和污染物中表达 (例如，颗粒物&lt；2.5𝜇m(PM2.5))会引起表观遗传和基因表达的变化。人们对此知之甚少 慢性污染暴露对哮喘儿童DNA甲基化及基因表达的影响 这种变化是否与哮喘加重有关。此外，尚不清楚是否可以避免污染。 建议(空气质量指数)会导致不同的DNA甲基化或基因表达。这 该提案将：1)确定PM2.5暴露与居民区靠近主干道之间的关联 (交通相关空气污染的指标)和(A)全基因组DNA甲基化和(B)在 哮喘儿童鼻(呼吸道)上皮细胞；2)鉴别DNA甲基化标志物或 表达与哮喘加重有关的基因(通过PM2.5或道路暴露水平)；以及 3)进行探索性分析，以评估环境保护局赞助的影响 AQI行为干预对哮喘儿童试验中DNA甲基化和基因表达的影响。目标 1-2使用NIH资助的两项已完成研究的现有数据。AIM 3使用来自飞行员的银行生物标本 对接受AQI干预的儿童哮喘行动计划(即临床护理)进行的随机临床试验。 这项提案解决了一个未得到满足的需求，即开发污染物诱发哮喘的“经济学”标记物 儿童的病情恶化。Rosser博士的职业发展计划为掌握统计基因组学提供了条件 方法和分析，并以临床试验管理和分析技能为基础。她做得很好，可以 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。这份职业 开发奖将为R01提供技能和初步数据，以寻求测试 表观遗传/基因标记物预测哮喘结果的风险和对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.