Prenatal Tobacco Smoke, Genetic and Epigenetic Changes, and Respiratory Health

描述(由申请人提供)：哮喘是儿童发病率的主要原因，正常的肺功能发育对儿童和随后的成人生活中的呼吸健康至关重要。我们已经开发了初步数据，突出了产前吸烟(PTS)暴露的不利影响。PTS暴露可永久性地改变发育中的肺和胎儿的免疫功能，增加患呼吸系统疾病的风险，了解这些影响的机制可能有助于阐明其他环境暴露的影响。科学家们已经清楚地证明，早期生命的环境和遗传因素都有助于哮喘的发病机制和肺功能。最近的研究强调了环境相关免疫功能和呼吸健康背后的遗传变异和表观遗传改变的重要性。我们提出的初步研究表明，在PTS的背景下，I型受体酪氨酸激酶(Tyro3、Ax1和Mer)家族的遗传和表观遗传变异在早期生命、肺功能和哮喘发病机制中具有潜在的重要性。为了提供一个有助于解决这一关键知识缺口的概念框架，我们建议对(Tyro3、Ax1和Mer)I型受体酪氨酸激酶家族进行表观遗传学-遗传学综合分析，以更好地了解PTS相关肺功能发育受损和哮喘风险增加的生物学机制。具体地说，该应用程序建立在Pi的K01项目的基础上，以进一步评估儿童健康研究(CHS)中的1500名受试者，CHS是一项关于南加州16个社区的空气污染物和呼吸健康的纵向研究。这项研究将利用现有的全面资源，包括全基因组关联数据、相关的出生记录和广泛的呼吸评估。该项目将重点放在基因家族上进行整合分析，因为这些基因在慢性炎症性疾病和自身免疫性疾病的发展中非常重要，我们的初步数据表明，表观遗传机制可能起到了作用。该建议将实现以下目的：(1)表征PTS暴露与基因甲基化的关系，并验证所观察到的关联；(2)探讨单倍型是否与基因甲基化或修改PTS相关的DNA甲基化；(3)表征PTS暴露与mi-R34a和miR-199a/b水平启动子甲基化的关系，这三个已知调节Ax1表达的miRNA，并进一步与它们的表达水平有关；(4)运用典型相关分析方法，全面了解PTS暴露、CpG甲基化、基因或miRNA表达、基因单倍型与哮喘及肺功能的关系。拟议的表观遗传学-遗传学综合分析与新生儿血斑(NBS)用于测量产前暴露和表观遗传学变化的新用途相结合，有望为研究各种具有早期环境起源的复杂人类疾病的表观遗传学机制提供强有力的途径。]

DESCRIPTION (provided by applicant): Asthma is a leading cause of childhood morbidity and normal lung function development is essential for respiratory health during childhood and subsequent adult life. We have developed preliminary data that highlight the adverse effects of prenatal tobacco smoke (PTS) exposure. PTS exposure can permanently alter the developing lung and fetal immune function, increasing risk for respiratory disease, and understanding the mechanisms of these effects may shed light on the effects of other environmental exposures. Scientists have clearly demonstrated both early-life environmental and genetic factors contribute to the pathogenesis of asthma and lung function. Recent studies highlight the importance of genetic variants and epigenetic alterations underlying environmentally-related immune function and respiratory health. We present preliminary studies showing the potential importance of genetic and epigenetic variation in the TAM (TYRO3, AXL, and MER) family of Type I receptor tyrosine kinases in early life lung function and asthma pathogenesis in the context of PTS. To provide a conceptual framework useful for addressing this critical knowledge gap, we propose an integrated epigenetic-genetic analysis of the TAM (TYRO3, AXL, and MER) family of Type I receptor tyrosine kinases to better understand the biological mechanisms underlying the impaired lung function development and increased risk of asthma associated with PTS. Specifically, this application builds on the PI's K01 project to further evaluate 1500 subjects in the Children's Health Study (CHS), a longitudinal study of air pollutant and respiratory health in 16 Southern California communities. The study will leverage an existing comprehensive resource that includes genome-wide association data, linked birth records, and extensive respiratory assessments. The project focuses on the TAM gene family for the proposed integrated analysis because these genes are important in the development of chronic inflammatory and autoimmune diseases and our preliminary data suggest epigenetic mechanisms may play a role. The proposal will accomplish the following aims: (1) characterize the association between PTS exposure and TAM gene DNA methylation and validate observed associations; (2) explore whether haplotypes are associated with TAM gene DNA methylation or modify the PTS-associated DNA methylation; (3) characterize the association between PTS exposure and promoter DNA methylation of mi-R34a and miR-199a/b levels, three miRNAs known to regulate AXL expression, and further relate to their expression levels; and (4) build a comprehensive picture of the inter- relationships between PTS exposure, CpG methylation, gene or miRNA expression, and haplotypes in the TAM genes in association with asthma and lung function using methods based on canonical correlation. The proposed integrated epigenetic-genetic analysis coupled with the novel use of newborn bloodspots (NBS) to measure prenatal exposure and epigenetic alterations is expected to offer a powerful approach to studying the epigenetic-genetic mechanism for various complex human diseases with early-life environmental origins.]