Inhaled environmental particles, pregnancy and neonatal allergy

吸入环境颗粒、妊娠和新生儿过敏

• 批准号: 8272704
• 负责人: ALEXEY V FEDULOV
• 金额: $ 24.9万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8272704
• 关键词: Address; Adoptive Transfer; Air Pollution; Allergic; Alveolar Macrophages; Antibodies; Asthma; Biogenesis; Biological Assay; Breathing; Child; Child health care; Data; Diesel Exhaust; Disease; Environment; Environmental Exposure; Estrogens; Faculty; Female; Fetus; Future; Gene Expression Profiling; Goals; Health; Hormones; Hypersensitivity; Immune; Immune response; Immunity; In Vitro; Inflammatory; Inhalation Exposure; Interleukin-4; Life; Literature; Lung; Maternal Exposure; Mediating; Mediator of activation protein; Mentors; Mentorship; Modeling; Molecular; Mothers; Mus; Neonatal; Newborn Infant; Ovalbumin; Phase; Predisposition; Pregnancy; Progesterone; Public Health; Recombinant Cytokines; Regulation; Research; Role; Serum; Testing; base; career; cytokine; environmental agent; eosinophilic inflammation; fetal; in utero; in vivo; insight; neutralizing antibody; novel; offspring; particle; pregnant; response; titanium dioxide; treatment effect; treatment strategy

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.

问题与试点数据：怀孕期间的环境暴露会影响未来的健康 成长的孩子，但具体机制尚不清楚。飞行员数据显示，母鼠的后代 怀孕期间暴露于柴油排气颗粒比正常婴儿更容易受到过敏的影响 母亲。持续不正确，这种效应也由对照，“惰性”二氧化钛颗粒引起。而且，“惰性” 颗粒实际上是孕妇小鼠的致病性/促插入性（同时导致未怀孕的最小作用 控件）。因此，怀孕会导致迄今为止肺部反应的变化 环境代理，提示中心假设：与妊娠相关的激素改变局部肺部先天 对吸入环境颗粒的免疫反应，导致系统性的细胞因子调节 后代免疫对过敏的敏感性更大。 特定目的1：表征怀孕小鼠对局部肺部和全身反应 环境颗粒，测试BAL分析中增强的Pro-Th2响应的预测，多重 血清和肺基因表达分析的细胞因子测定。特定目标2：表征 肺泡巨噬细胞（AM）对颗粒反应的怀孕激素，测试了以下预测。 孕激素和雌激素促进了对体外和体内颗粒的促进pro-Th2 AM反应。具体目标3; 通过中和测试Th2细胞因子在怀孕期间颗粒介导的作用中的因果作用 抗体和细胞因子治疗策略。 意义：严格的指导（AIM 1）将为候选人做好过渡到独立的准备（Aims 2和3）并继续在教师一级发展他在环境疾病方面的研究生涯。这 研究将为哮喘和应用的哮喘生命起源的基本问题提供新的见解 环境代理如何介导子宫效应的问题。