Prenatal Programming of Neonatal Asthma Susceptibility

新生儿哮喘易感性的产前规划 摘要/项目描述 问题和假设：哮喘开始于生命早期，与免疫功能障碍有关 对过敏的反应。人类流行病学确定“产前规划”是哮喘易感性的原因 通过母亲哮喘的危险因素。我们的母体过敏试验数据显示，新生儿树突状细胞 细胞(DC)是哮喘易感性的关键细胞因子，因为过继转移哮喘的DC- 易感的幼鼠会在其他情况下正常的幼鼠中引起新的哮喘风险。全基因组DNA分析 甲基化显示，与对照组相比，易感哮喘的树突状细胞中的甲基化存在显著差异。除了……之外 母亲哮喘、其他环境暴露(如烟草烟雾、空气污染)会导致新生儿哮喘 风险，但机制仍然没有得到很好的描述。我们在正常母鼠身上的实验研究表明， 各种环境应激源都会导致婴儿更容易患上过敏性呼吸道 疾病。我们的中心假设是多种环境应激源导致早期哮喘 新生儿树突状细胞通过表观遗传修饰的易感性，从而导致前哮喘偏斜 免疫反应。 具体目标：目标1将使用DC的收养转移来测试多次母亲暴露的假设 (空气污染、化学性皮炎、压力)都会产生一种改变的易患哮喘的DC，类似于 观察卵清蛋白诱导的过敏性哮喘母亲的后代。DC亚群将进一步 以优化表观遗传分析为特征。AIM 2将使用全基因组和有针对性的表观遗传分析来 测试这样的预测：易感哮喘的DC将分享与偏向亲本有关的表观遗传标记。 哮喘DC表型。目标3将检验这一假设，即无数母亲的共同机制 “环境应激源”是一种经胎盘的应激激素反应，它导致表观遗传和 “哮喘易感”新生儿DC的功能变化 影响和意义：计划中的研究将确定孕妇如何在多种环境中暴露 母亲会导致哮喘风险，并将为公共卫生和治疗干预提供目标。

Prenatal Programming of Neonatal Asthma Susceptibility Abstract/Project Description Problem and Hypothesis: Asthma begins in early life, and is linked to immune dysfunction that skews responses towards allergy. Human epidemiology identifies 'prenatal programming' for asthma susceptibility through the risk factor of maternal asthma. Our pilot data in maternal allergy reveal that the neonatal dendritic cell (DC) is the critical cellular agent of asthma susceptibility, since adoptive transfer of DCs from asthma- susceptible juvenile mice causes new asthma risk in otherwise normal pups. Genome-wide analysis of DNA methylation shows substantial differences in 'asthma-susceptible' DCs compared to controls. In addition to maternal asthma, other environmental exposures (e.g. tobacco smoke, air pollution) cause neonatal asthma risk, but mechanisms remain poorly characterized. Our experimental studies in normal mother mice show that various 'environmental stressors' all result in babies that are more susceptible to developing allergic airway disease. Our central hypothesis is that multiple environmental stressors cause early life asthma susceptibility through epigenetic modifications in neonatal DCs, which confer pro-asthmatic skewing of immune responses. Specific Aims: Aim 1 will use adoptive transfer of DCs to test the postulate that multiple maternal exposures (air pollution, chemical dermatitis, stress) all produce an altered 'asthma-susceptible' DC, similar to that observed in offspring of mothers with OVA-induced allergic asthma. DC subpopulations will be further characterized to optimize epigenetic analyses. Aim 2 will use genome-wide and targeted epigenetic analysis to test the prediction that 'asthma-susceptible' DCs will share epigenetic marks linked to skewing towards a pro- asthmatic DC phenotype. Aim 3 will test the hypothesis that the shared mechanism for myriad maternal 'environmental stressors' is a transplacental stress hormone response which causes the epigenetic and functional changes seen in 'asthma-susceptible' neonatal DCs Impact & Significance: The planned studies will identify how multiple environmental exposures of pregnant mothers cause asthma risk, and will provide targets for public health and therapeutic interventions.