Prenatal Programming of Neonatal Asthma Susceptibility

描述(申请人提供)：哮喘开始于生命早期，与免疫功能障碍有关，免疫功能障碍使过敏反应偏向。人类流行病学通过母亲哮喘的危险因素确定了哮喘易感性的“产前规划”。我们在母体过敏方面的初步数据显示，新生儿树突状细胞(DC)是哮喘易感性的关键细胞因子，因为过继转移哮喘易感幼鼠的DC会在其他正常的幼鼠中产生新的哮喘风险。全基因组DNA甲基化分析显示，与对照组相比，易感哮喘的树突状细胞存在显著差异。除母亲哮喘外，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，但机制仍不明确。我们在正常母鼠身上进行的实验研究表明，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，多种环境应激源通过新生儿树突状细胞的表观遗传修饰导致早期哮喘易感性，从而导致免疫反应的亲哮喘倾斜。具体目标：Aim 1将使用树突状细胞的收养转移来测试这样的假设，即母亲多次暴露(空气污染、化学性皮炎、压力)都会产生一种改变的“哮喘易感”DC，类似于在患有OVA诱导的过敏性哮喘的母亲的后代中观察到的情况。DC亚群将进一步表征，以优化表观遗传分析。AIM 2将使用全基因组和有针对性的表观遗传学分析来验证这样的预测，即“哮喘易感”DC将分享与偏向哮喘前期DC表型有关的表观遗传标记。目的3将检验这样一个假设，即众多母亲的环境应激源的共同机制是一种经胎盘的应激激素反应，该应激激素反应导致了易哮喘的新生儿DC的表观遗传学和功能变化&意义：计划中的研究将确定孕妇的多种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靶点。公共卫生相关性：计划中的研究将确定孕妇暴露在多种环境中是如何导致哮喘风险的，并将为公共卫生和治疗干预提供目标。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.