Prenatal PM2.5 and programming of respiratory outcomes: Placental biomarkers and effect modification by stress

项目摘要 我是一名内科科学家，主要研究呼吸系统疾病的编程 产前/早期环境暴露，如空气污染和母亲压力，特别关注 母胎界面的编程机制，即胎盘。使用研究链接环境 空气污染对儿童呼吸道疾病的影响，这一提议的目标是为日益增长的研究增加联系 城市空气污染物、压力和呼吸发育，通过识别敏感的暴露和 鉴定新的线粒体和端粒生物标志物，宫内暴露可能通过这些生物标志物发挥作用 影响未来的呼吸系统发育。 通过正式的课程学习和专家指导，这个奖项将使我能够发展知识 和技能，成为一名独立的跨学科环境健康科学家，并实现 我的长期职业目标：建立一个有竞争力和成功资助的项目来研究累积 环境暴露(例如，空气污染/压力)对生物机制规划的影响 与儿童慢性疾病有关。虽然这个奖项关注的是呼吸结果，但值得注意的是 所获得的知识和技能将广泛适用于一系列儿童健康结果，因为 大量有线粒体和端粒支持的儿童期疾病(如哮喘、肥胖、 心血管疾病、神经认知结果)。具体地说，我将1)接受空气污染方面的培训， 在纵向队列研究设计的背景下进行压力评估；2)接受培训和指导 选择和解释线粒体和端粒分析；3)接受高级培训 了解剂量-反应和时间的定量方法(例如，非线性分布滞后模型) 空气污染与健康之间的关系。 这项拟议的研究将是第一次调查产前环境空气的易损性窗口。 污染暴露对儿童呼吸道发育的影响及线粒体和端粒生物标志物的研究 在目标组织(例如胎盘)中与产前环境暴露(例如环境空气污染)相关 和应激)和早期呼吸表型。我们将使用每日空气污染暴露量，这些空气污染暴露量来自经过验证的 时空建模方法与分布式滞后方法相结合识别空气敏感窗 污染暴露对呼吸道表型的影响。我们将使用最先进的分析胎盘线粒体和 端粒生物标志物：1)已被证明可被环境暴露改变；以及2)反映 妊娠期间累积的氧化损伤。这项研究也极具成本效益，因为我们将利用 现有表型良好的城市和种族混合妊娠队列的资源[围产期 环境与发展研究(PEDS)]现有环境暴露(空气污染和压力)， 协变量和表观基因组数据。

Project Summary I am a physician-scientist with a primary research interest in the programming of respiratory diseases by prenatal/early-life environmental exposures, such as air pollution and maternal stress, with particular interest in the programming mechanisms at the maternal-fetal interface, i.e., the placenta. With research linking ambient air pollution to childhood respiratory disease, the goal of this proposal is to add to the growing research linking urban air pollutants, stress, and respiratory development by identifying sensitive windows of exposure and identifying novel mitochondrial and telomere biomarkers through which in utero exposures may be operating to impact future respiratory development. Through formal coursework and expert mentoring, this award will enable me to develop the knowledge and skills necessary to become an independent transdisciplinary environmental health scientist and achieve my long-term career goals: to establish a competitive and successfully funded program to study the cumulative effects of environmental exposures (e.g., air pollution/stress) on the programming of biological mechanisms related to chronic childhood conditions. While this award focuses on respiratory outcomes, it is worth noting that the knowledge and skills obtained will be broadly applicable to a range of child health outcomes given the large number of childhood conditions with mitochondrial and telomere underpinnings (e.g., asthma, obesity, cardiovascular disease, neurocognitive outcomes). Specifically, I will 1) obtain training in air pollution and stress assessment in the context of a longitudinal cohort study design; 2) receive training and guidance in selecting and interpreting mitochondrial and telomere analyses; and 3) undergo extensive training in advanced quantitative methods (e.g. non-linear distributed lag models) to understand dose-response and temporal relationships between air pollution and health. The proposed study will be the first to investigate windows of vulnerability to prenatal ambient air pollution exposure on child respiratory development and to investigate mitochondrial and telomere biomarkers in a target tissue (e.g. placenta) with respect to prenatal environmental exposures (e.g. ambient air pollution and stress) and early respiratory phenotypes. We will use daily air pollution exposures derived from a validated spatio-temporal modeling approach coupled with distributed lag methods to identify sensitive windows of air pollution exposure on respiratory phenotype. We will use state-of-art analyses of placental mitochondrial and telomere biomarkers that: 1) have been shown to be altered by environmental exposures; and 2) reflect cumulative oxidative damage over gestation. This study is also highly cost effective as we will leverage the resources of an existing well-phenotyped urban and ethnically-mixed pregnancy cohort [Perinatal Environmental and Development Study (PEDS)] with extant environmental exposure (air pollution and stress), covariate, and epigenome data.