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

慢性室外空气污染、气道上皮“组学”和儿童哮喘恶化

• 批准号: 10470284
• 负责人: Franziska Rosser
• 金额: $ 16.03万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10470284
• 关键词: Address; Air; Air Pollution; Ancillary Study; Asthma; Behavior Therapy; Behavioral; Biological Markers; Biological Specimen Banks; Caring; Cause of Death; Child; Child Care; Child health care; Childhood Asthma; Chronic; Clinical; Clinical Management; Clinical Trials; Cross-Sectional Studies; DNA; DNA Methylation; Data; Development; Development Plans; Disease; Emergency Situation; Environment; Epidemiology; Epigenetic Process; Evidence based intervention; Exposure to; Funding; Gene Expression; Genes; Genomics; Goals; Government; Health Care Costs; Health Personnel; Hospitalization; Individual; Intervention; K-Series Research Career Programs; Knowledge; Lead; Lung diseases; Mentors; Methods; Methylation; Modeling; Nasal Epithelium; Nose; Nutritional; Outcome; Particulate Matter; Pathogenesis; Pilot Projects; Play; Policies; Pollution; Positioning Attribute; Predisposition; Preparation; Proxy; Puerto Rican; Randomized Clinical Trials; Recommendation; Research; Risk; Sampling; Schools; Statistical Data Interpretation; Statistical Methods; Susceptibility Gene; Testing; Therapeutic; Time; Tissue-Specific Gene Expression; Tissues; Training; United States Environmental Protection Agency; United States National Institutes of Health; Visit; Vitamin D; Work; airway epithelium; ambient air pollution; asthma exacerbation; care providers; career development; clinical care; clinical practice; cohort; design; differential expression; epigenetic variation; ethnic diversity; fine particles; genome-wide; health care service utilization; improved; indexing; insight; methylation biomarker; novel; novel therapeutics; pollutant; predictive marker; predictive tools; prevent; response; skill acquisition; skills; tool; traffic-related air pollution; transcriptomics

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.

摘要： 室外空气污染是儿童哮喘恶化的已知原因，但在常规治疗中很少得到解决。 哮喘护理科学知识和临床实践之间的差距必须得到解决，以改善 儿童哮喘的治疗虽然没有“安全”的污染水平，但个人对空气的敏感性 污染和哮喘恶化在儿童中各不相同。儿童哮喘急性发作很难预测， 导致缺课和父母工作日，并大大增加了医疗保健利用率和成本。它 目前尚不清楚我们目前的哮喘治疗是否能预防污染引起的哮喘加重。污染减排 政策是最好的干预措施，但在所有人都能保证“清洁”空气之前， 需要查明最有可能受污染引起的病情恶化影响的儿童，以制定干预措施。 气道上皮是研究组学和开发新的污染诱导的生物标志物的理想组织 哮喘急性发作，因为哮喘易感基因在气道上皮和污染物中表达 (e.g.颗粒物<2.5μ m（PM2.5））诱导表观遗传和基因表达变化。知之甚少 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 空气质量指数（AQI）的差异会导致DNA甲基化或基因表达的差异。这 该提案将：1）确定PM2.5暴露与住宅区靠近主要道路之间的关联 （交通相关空气污染的代表）和（a）全基因组DNA甲基化和（B）基因表达， 哮喘儿童的鼻（气道）上皮; 2）鉴定差异DNA甲基化标记物或 与哮喘急性发作相关的表达基因（通过暴露于PM2.5或道路）;以及 3)进行探索性分析，以估计环境保护局赞助的 AQI行为干预对哮喘儿童DNA甲基化和基因表达的影响旨在 1-2使用来自两个完成的NIH资助的研究的现有数据。AIM 3使用了一名飞行员的生物样本库 接受哮喘行动计划（即临床护理）AQI干预的儿童的随机临床试验。 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”标记物 儿童病情加重。Rosser博士的职业发展计划规定掌握统计基因组学 方法和分析，并建立在临床试验管理和分析技能。她很适合 她提出的研究提供了流行病学背景，空间建模技能和试点数据。这个职业 发展奖将为R 01提供技能和初步数据，以测试是否 表观遗传/基因标记物可预测哮喘结局的风险和对AQI干预的反应。