Prenatal Programming of Neonatal Asthma Susceptibility

描述（由申请人提供）：哮喘始于生命早期，与免疫功能障碍有关，导致对过敏的反应偏斜。人类流行病学通过母体哮喘的危险因素确定了哮喘易感性的“产前规划”。我们在母体过敏中的试验数据显示，新生儿树突状细胞（DC）是哮喘易感性的关键细胞因子，因为从哮喘易感的幼年小鼠中过继转移DC会导致其他正常幼鼠出现新的哮喘风险。DNA甲基化的全基因组分析显示，与对照组相比，“哮喘易感”dc存在实质性差异。除孕产妇哮喘外，其他环境暴露（如烟草烟雾、空气污染）也会导致新生儿哮喘风险，但其机制尚不清楚。我们对正常母鼠的实验研究表明，各种“环境压力源”都会导致婴儿更容易患上过敏性气道疾病。我们的中心假设是，多种环境压力因素通过新生儿dc的表观遗传修饰导致早期哮喘易感性，这赋予了促哮喘的免疫反应扭曲。具体目的：目的1将使用DC的过继性转移来验证这样的假设，即多次母体暴露（空气污染、化学皮炎、压力）都会产生改变的“哮喘易感”DC，类似于在ova诱发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将使用全基因组和靶向表观遗传分析来测试“哮喘易感”DC将共享与向哮喘前DC表型倾斜相关的表观遗传标记的预测。目标3将验证无数母体“环境压力源”的共同机制是经胎盘应激激素反应的假设，该反应导致“哮喘易感”新生儿DCs的表观遗传和功能变化。影响和意义：计划中的研究将确定孕妇的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。公共卫生相关性：计划中的研究将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): 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.