Childhood Allergy and the NeOnatal Environment (CANOE) ECHO Pediatric Follow-Up and New Enrollment

项目摘要 哮喘是一种复杂的、异质性的疾病，遗传和环境因素都会导致哮喘 疾病。上皮屏障是环境暴露和宿主之间的界面。基因- 环境相互作用研究表明，早期生活暴露会改变哮喘的遗传风险，并且 表观遗传变化，如DNA甲基化(DNaM)可能介导这些效应。此外，上皮性 转录变化与儿童哮喘有关。我们建议使用这两种强大的技术来 提供从环境暴露到哮喘发病的机械性联系。我们假设暴露在 在与社区(空气污染、附近的绿地)和个人有关的上皮屏障 (微生物组)改变上皮dNaM和转录反应以促进哮喘的发展。至 评估这一假设，我们将利用Echo Cohort协议3.0来确定产前和早期 生活、个人和邻里层面的暴露促进婴儿期鼻上皮的变化 喘息的发展(目标1)，确定这些暴露如何，包括皮肤微生物组， 影响皮肤上皮变化以促进特应性皮炎和喘息(目标2)，并阐明如何 个体和邻里特征自始至终影响着母亲鼻部的表观遗传变化 怀孕，以及这些变化与儿童过敏性疾病的关系(目标4)。最后，我们将跟随 现有的ECHO参与者招募了350名孕妇和50名先入为主的分娩妇女(对于 在400个新生儿中)进入回声队列方案3.0(目标3)。重要的是，在整个提案中，我们寻求 通过确定导致健康差异的机制来理清可能导致健康差异的因素 暴露(经常与种族联系在一起)会导致哮喘。我们将识别出精确的分子 诊断和预防的目标。该信息可用于(1)建立非侵入性生物标志物 (通过鼻拭子或皮肤拭子)以识别有哮喘风险的婴儿，(2)根据以下情况制定治疗策略 改变微生物定植或上皮基因表达的模式以促进健康，以及(3)确定 不利于健康差距的可采取行动的暴露，以进行干预。

PROJECT ABSTRACT Asthma is a complex, heterogenous condition with both genetic and environmental factors contributing to disease. The epithelial barrier is the interface between environmental exposures and the host. Gene- environment interaction studies demonstrate that early life exposures modify genetic risks in asthma, and epigenetic changes, such as DNA methylation (DNAm) may mediate these effects. Additionally, epithelial transcriptional changes link to childhood asthma. We propose to use both of these powerful technologies to provide a mechanistic link from environmental exposure to asthma inception. We hypothesize that exposures at the epithelial barrier related to the community (air pollution, nearby green space) and the individual (microbiome) alter epithelial DNAm and transcriptional responses to promote the development of asthma. To evaluate this hypothesis, we will leverage the ECHO Cohort protocol 3.0 to determine how prenatal and early life individual and neighborhood level exposures contribute to nasal epithelial changes in infancy to promote the development of wheezing (aim 1), determine how the these exposures, including the skin microbiome, influence skin epithelial changes to promote atopic dermatitis and wheezing (aim 2), and elucidate how individual and neighborhood characteristics influence maternal nasal epigenetic changes throughout pregnancy, and how these changes relate to allergic diseases in the child (aim 4). Finally, we will follow existing ECHO participants and recruit 350 pregnant women and 50 women preconception that give birth (for a of total 400 births) into ECHO Cohort protocol 3.0 (aim 3). Importantly, throughout this proposal, we seek to disentangle factors that may underlie health disparities by identifying the mechanisms by which environmental exposures (that are often associated and conflated with race) cause asthma. We will identify precise molecular targets for diagnosis and prevention. This information can be used to (1) establish non-invasive biomarkers (from nasal or skin swabs) to identify infants at risk for asthma, (2) develop treatment strategies based on altering patterns of microbial colonization or epithelial gene expression to promote health, and (3) identify actionable exposures that underly health disparities for intervention.