Inhaled environmental particles, pregnancy and neonatal allergy

问题和试点数据：怀孕期间暴露在环境中会影响妇女未来的健康 儿童正在发育中，但具体机制尚不清楚。试点数据显示，母鼠的后代 怀孕期间接触柴油废气微粒比正常婴儿更容易过敏 母亲们。值得注意的是，这种影响也是由控制“惰性”二氧化钛颗粒引起的。此外，“惰性” 颗粒实际上对怀孕的小鼠是致病的/促炎的(而对未怀孕的小鼠影响很小 控制)。因此，怀孕导致了迄今为止尚未被认识到的肺部反应的变化 环境因素，促使中心假说：与怀孕相关的激素改变局部肺固有 对吸入环境颗粒物的免疫反应，导致发育中全身细胞因子的调节 后代对更易过敏的状态具有免疫力。 具体目标1：描述妊娠小鼠对以下物质的局部肺和全身反应 环境颗粒物，在BAL分析中测试增强的前Th2反应的预测，多重 血清和肺基因表达谱的细胞因子分析。具体目标2：确定 妊娠激素对肺泡巨噬细胞(AM)颗粒的反应，验证了预测 黄体酮和雌激素在体外和体内都能促进前Th2 AM对颗粒的反应。具体目标3； 用中和法检测Th2细胞因子在妊娠颗粒介导效应中的因果作用 抗体和细胞因子治疗策略。 意义：严格的指导(目标1)将为候选人向独立过渡(目标1)做好准备 2和3)，并继续在教职员工层面上发展他的环境疾病研究事业。这 研究将为哮喘的早期生命起源及其应用这一基本问题提供新的见解 环境因素如何在子宫影响中起调节作用的问题。

Problem & 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. Remaricably, this effect is also caused by control, 'inert' titanium dioxide particles. Moreover, 'inert' particles are actually pathogenic/pro-infiammatory in pregnant mice (while causing minimal effects in nonpregnant 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 eariy life origins of asthma and the applied question of how environmental agents mediate in utero effects.