Prenatal Programming of Neonatal Asthma Susceptibility

描述（由申请人提供）：人类流行病学通过风险因素如母体哮喘或环境暴露（如二手烟）确定哮喘易感性的“产前规划”，但机制尚不清楚。我们对小鼠的实验研究表明，各种“环境压力因素”（例如，“哮喘”母鼠体内的过敏原、空气污染颗粒、压力）都会导致母亲的婴儿更容易患上过敏性呼吸道疾病。这种哮喘易感性是由新生儿树突状细胞（DC）介导的，与明显的表观遗传变化（DNA甲基化）有关。我们的R01项目是研究小鼠哮喘易感性的产前编程机制和表观遗传学。我们的ViCTER项目将把这些研究扩展到人类生物学。核心假设是人类新生儿dc和肺上皮细胞的表观遗传修饰与哮喘易感性有关。我们的ViCTER研究将通过三个具体目标将动物模型数据转化为人类研究。具体目标：Aim 1将与联盟成员密切合作，将主要申请人对哮喘风险产前规划的表观基因组分析扩展到相关人类样本。本目标将使用全基因组甲基化阵列来分析目标2和目标3中获得的样品的表观遗传变化。Aim 2将专门比较“哮喘易感”与正常人类新生儿树突状细胞的DNA甲基组。我们将对人类新生儿脐带血dc中的DNA甲基化标记进行靶向和全基因组分析，这些dc来自奈良（日本）的联盟成员，来自哮喘、吸烟或正常母亲。Aim 3将比较从“哮喘易感”和正常人类胎儿肺中分离出来的另一种对哮喘至关重要的细胞类型——肺气道上皮细胞的关键基因的DNA甲基化谱。该联盟成员（波士顿，马萨诸塞州）将使用正常（对照组）、吸烟者（二手烟对胎儿的影响）或哮喘母亲在选择性流产后保存的正常胎儿肺组织。在激光捕获显微解剖（LCM）分离气道上皮后，比较稳定的DNA甲基化标记将评估与哮喘易感性相关的靶向表观遗传变化。这些ViCTER研究将我们的R01项目扩展到人类病理生物学，验证中心假设，并为未来环境暴露对产前表观遗传编程的研究奠定基础。这项小鼠和人类联合研究将有助于确定孕妇多重环境暴露如何导致哮喘风险，并将为公共卫生和治疗干预提供目标。

DESCRIPTION (provided by applicant): Human epidemiology identifies 'prenatal programming' for asthma susceptibility through risk factors such as maternal asthma or environmental exposures (e.g. second-hand smoke), but mechanisms remain unclear. Our experimental studies in mice show that various 'environmental stressors' (e.g., allergens in 'asthmatic' mother mice, air pollution particles, stress) all result in a mother whose babies are more susceptible to developing allergic airway disease. This asthma susceptibility is mediated by the neonatal dendritic cell (DC), in association with distinct epigenetic changes (DNA methylation). Our R01 project is pursuing the mechanisms and epigenetics of prenatal programming of asthma susceptibility in mice. Our ViCTER program will extend these investigations into human biology. The central hypothesis is that epigenetic modifications in human neonatal DCs and lung epithelial cells are linked to asthma susceptibility. Our ViCTER research will translate the animal model data into human studies through three specific aims. Specific Aims: Aim 1 will extend the lead applicant's epigenomic analysis of prenatal programming of asthma risk to relevant human samples, in close collaboration with the consortium members. This aim will use genome-wide methylation arrays to analyze epigenetic changes in samples obtained in aims 2 and 3. Aim 2 will specifically compare the DNA methylome of 'asthma-susceptible' versus normal human neonatal dendritic cells. We will perform targeted and genome-wide analysis of DNA methylation marks in human neonatal cord blood DCs, obtained from the consortium members in Nara (Japan), from well-characterized asthmatic, smoking or normal mothers. Aim 3 will compare DNA methylation profiles in key genes of another cell type critical in asthma, the lung airway epithelial cell, isolated from 'asthma-susceptible' versus normal human fetal lungs. The consortium members (Boston, MA) will use normal fetal lung tissue, archived after elective abortion, from mothers who are normal (controls), smokers (second-hand smoke effects on fetus), or asthmatic. After laser-capture microdissection (LCM) to isolate airway epithelium, comparison of the stable DNA methylation marks will evaluate targeted epigenetic changes linked to asthma susceptibility. These ViCTER studies will extend our R01 project into human pathobiology, test the central hypothesis and develop the foundation for future studies of prenatal epigenetic programming by environmental exposures. The combined mouse and human studies will help identify how multiple environmental exposures of pregnant mothers cause asthma risk, and will provide targets for public health and therapeutic interventions.