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

基本信息

批准号：
10281680
负责人：
Franziska Rosser
金额：
$ 16.01万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
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/10281680
关键词：
Address Air Air Pollution Ancillary Study Asthma Behavior Therapy Behavioral Biological 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

项目摘要

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.

抽象的：室外空气污染是童年哮喘加重的已知原因，但很少在常规中解决哮喘护理。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医疗保健。虽然没有“安全”的污染水平，但个人敏感儿童的污染和哮喘恶化各不相同。童年哮喘恶化很难预测，导致错过学校和父母的工作日，并为医疗保健利用和成本做出了重大贡献。尚不清楚我们目前的哮喘治疗是否可以防止污染引起的加重。减少污染政策是最好的干预措施，但直到所有人都保证“清洁”空气之前，开发生物标志物需要确定有污染引起的加重风险的儿童以制定干预措施。气道上皮是研究幻象并开发污染引起的新生物标志物的理想组织哮喘恶化，作为哮喘的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））诱导表观遗传和基因表达变化。对慢性污染暴露对哮喘儿童DNA甲基化和基因表达的影响这种变化是否与哮喘加重有关。此外，未知是否避免污染建议（空气质量指数（AQI））导致差异DNA甲基化或基因表达。这提案将：1）确定接触PM2.5与居民接近主要道路之间的关联（用于交通相关的空气污染的代理）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）确定不同的DNA甲基化标记或表达与哮喘患病有关的基因（通过暴露于PM2.5或道路）；和 3）进行探索性分析，以估算由环境保护机构赞助的影响哮喘儿童试验的DNA甲基化和基因表达的AQI行为干预。目标 1-2使用两项已完成的NIH资助研究中的现有数据。 AIM 3使用飞行员的银行生物测量接受AQI干预的儿童的随机临床试验（即临床护理）。该提议解决了未满足的需求，即污染物引起的哮喘的“ imic”标记儿童加剧。罗瑟博士的职业发展计划掌握了统计基因组的掌握方法和分析，并以临床试验管理和分析技能为基础。她的位置很好她提出的研究鉴于流行病学背景，具有空间建模的技能和试验数据。这个职业开发奖将为R01提供技能和初步数据，以试图测试是否是否表观遗传/基因标记物可以预测哮喘结局的风险和对AQI干预的反应。