Prenatal diesel exposure and adult onset asthma

描述(申请人提供)：哮喘一直被认为是一种复杂的遗传性疾病，一生都会受到环境因素的影响。然而，最近的证据表明，哮喘的发病可能受到宫内环境暴露的影响。接触柴油废气颗粒物(DEP)与肺形成减少有关。此外，较高的DEP暴露与对花粉致敏的风险更大，以及被认为是过敏性哮喘或过敏性哮喘的Th2细胞因子的上调有关。但是，尽管越来越多的证据表明，产前接触变应原会导致哮喘相关表型的后续发病，但产前接触DEP对哮喘后期发病的调节作用尚未阐明。此外，其机制，包括产前接触DEP对肺发育和差异基因表达的影响，尚未被研究。我们假设，产前接触柴油会增加成人哮喘发病的风险。我们的策略将是通过使用可靠的抗原特异性致敏的小鼠模型来研究产前DEP暴露于哮喘的影响，并使用它们来研究与成人哮喘相关的表型，包括增加的IgE产生、对Th2血统的承诺、呼吸道高反应性和气道重塑。我们预测，产前接触DEP将导致IgE类转换和Th2分化增加，从而增加成人哮喘发病的风险。我们还预测，在子宫内暴露于DEP后检测到的肺发育变化和/或差异基因表达将与成人哮喘相关。我们预计，对子宫内环境刺激的免疫和遗传反应的重要性及其对后来疾病的影响的研究，可能有助于更好地理解环境污染物在哮喘发病中的作用，并最终制定更好的预防策略。具体地说，我们建议：目标1：确定产前接触DEP是否会增加后代的IgE产生和对Th2血统的承诺。目的2：确定胎儿期接触DEP是否与发育中的肺上皮细胞分化改变有关。目的3：确定胎儿期接触DEP是否与成年小鼠的气道高反应性或气道重塑有关。目的：确定宫内柴油暴露后的差异基因表达，以及产前柴油暴露后的差异基因表达是否与成人哮喘相关。

DESCRIPTION (provided by applicant): Asthma has long been considered a complex genetic disease that is subject to environmental triggers experienced over a lifetime. Yet more recent evidence suggests that the onset of asthma may be modulated by intra-uterine environmental exposures. Exposure to diesel exhaust particles (DEP) has been associated with decreased lung formation. In addition, higher DEP exposure has been associated with a greater risk of becoming sensitized to pollen, and with up regulation of Th2 cytokines thought to underly atopy or allergic asthma. But despite growing evidence implicating prenatal allergen exposure to the subsequent onset of asthma-related phenotypes, the modulatory role of prenatal exposure to DEP to the later onset of asthma has not been elucidated. Furthermore, the mechanisms, including the impact of prenatal DEP exposure on lung development and differential gene expression, have not been studied. We hypothesize that prenatal diesel exposure can increase the risk for adult-onset asthma. Our strategy will be to study the effects of prenatal DEP exposure to asthma by employing reliable mouse models for antigen-specific sensitization and using them to study phenotypes associated with adult asthma, including augmented IgE production, commitment to the Th2 lineage, airway hyperreactivity, and airway remodeling. We predict that prenatal DEP exposure will lead to increased IgE class switching and Th2 differentiation, thereby promoting the risk for adult-onset asthma. We also predict that lung developmental changes and/or differential gene expression detected following in utero exposure to DEP will be associated with adult asthma. We anticipate that a study of the importance of immunologic and genetic responses to intra-uterine environmental stimuli, and their impacts on later disease, could lead to a better understanding of the role of environmental pollutants to asthma pathogenesis, and ultimately better strategies for prevention. Specifically, we propose to: Aim 1: Determine whether prenatal DEP exposure augments IgE production and commitment to Th2 lineage in the offspring. Aim 2: Determine whether prenatal DEP exposure is associated with altered epithelial cell differentiation in the developing lung. Aim 3: Determine whether prenatal DEP exposure is associated with increased airway hyper reactivity or airway remodeling in adult mice. Aim 4: Determine a) the differential gene expression following in utero diesel exposure, and b) whether differential gene expression following prenatal diesel exposure is associated with adult asthma.