Inhaled environmental particles, pregnancy and neonatal allergy

描述（由申请人提供） 问题和试点数据：怀孕期间的环境暴露可能会影响发育中儿童的未来健康，但具体机制尚不清楚。试点数据显示，怀孕期间暴露于柴油机尾气颗粒的母鼠的后代比正常母亲的婴儿更容易过敏。值得注意的是，这种效果也是由对照的“惰性”二氧化钛颗粒引起的。 此外，“惰性”颗粒在妊娠小鼠中实际上是致病性/促炎性的（而在非妊娠对照中引起最小的影响）。 因此，妊娠导致了迄今为止尚未认识到的肺对环境因子的反应变化，促使了中心假设：妊娠相关激素改变了局部肺对吸入环境颗粒的先天免疫反应，导致系统性细胞因子调节发育中的后代免疫力，使其对过敏更敏感。 具体目标1：表征妊娠小鼠对环境颗粒物的局部肺和全身反应，测试BAL分析、血清和肺基因表达谱的多重细胞因子测定中增强的pro-Th 2反应的预测。 具体目标2：为了表征妊娠激素对肺泡巨噬细胞（AM）对颗粒物的反应的影响，测试孕酮和雌激素在体外和体内促进Pro-Th 2 AM对颗粒物的反应的预测。 具体目标3：通过中和抗体和细胞因子治疗策略，检测Th 2细胞因子在妊娠期间颗粒介导效应中的因果作用。 重要性：严格的指导（目标1）将准备过渡到独立的候选人（目标2和3），并继续发展他的研究生涯在环境疾病的教师水平。这项研究将提供新的见解的基本问题的早期生命起源的哮喘和应用问题的环境因素如何介导子宫内的影响。

DESCRIPTION (provided by applicant) Problem and Pilot Data: Environmental exposures during pregnancy can influence the future health of the developing child, but specific mechanisms are unknown. Pilot data show that offspring of mother mice exposed during pregnancy to diesel exhaust particles are more susceptible to allergy than babies of normal mothers. Remarkably, this effect is also caused by control, "inert" titanium dioxide particles. Moreover, '"inert" particles are actually pathogenic/pro-inflammatory in pregnant mice (while causing minimal effects in non pregnant controls). Hence, pregnancy causes a heretofore unrecognized change in lung responses to environmental agents, prompting the central hypothesis: pregnancy-related hormones alter local lung innate immune responses to inhaled environmental particles, leading to systemic cytokine modulation of developing offspring immunity to a state of greater susceptibility to allergy. Specific aim 1: To characterize the local pulmonary and systemic response of pregnant mice to environmental particles, testing the prediction of enhanced pro-Th2 responses in BAL analysis, multiplex cytokine assays of serum and lung gene expression profiling. Specific aim 2: To characterize effects of pregnancy hormones on the alveolar macrophage (AM) response to particles, testing the prediction that progesterone and estrogen promote pro-Th2 AM responses to particles in vitro and in vivo. Specific aim 3: To test the causal role of Th2 cytokines in particle-mediated effects during pregnancy by neutralizing antibody and cytokine treatment strategies. Significance: Rigorous mentorship (aim 1) will prepare the candidate for transition to independence (Aims 2 and 3) and continue developing his research career in environmental disease at a faculty level. This research will provide novel insights into the basic question of early life origins of asthma and the applied question of how environmental agents mediate in utero effects.