Impact of Early Life Diesel Exposure on Immune Patterning and Lung Structure/Func

描述（由申请人提供）： 哮喘是一种气道慢性炎症性疾病，是一个主要的公共卫生问题，特别是在儿童中，仅在美国就影响了超过900万儿童（13%）。研究指出，空气污染，包括交通排放，在哮喘的发展和哮喘症状的表达中起着重要作用。目前的建议是基于我们最近在辛辛那提儿童过敏和空气污染研究（CCAAPS）纵向出生队列中的发现，该研究表明，婴儿期柴油机排气颗粒（DEP）暴露以剂量依赖性方式赋予喘息风险。虽然DEP暴露和喘息/哮喘结果之间的联系已在许多研究中报道，但这种联系的机制仍不清楚。显然，在生命早期有一个关键时期，暴露会对健康产生重大影响。重要的是，在此期间，肺发育也在发生。描述生命早期暴露于空气污染和过敏原影响哮喘长期风险的机制很重要，因为这些因素可以控制。与正常人相比，哮喘儿童随着年龄的增长肺功能下降更快，观察到的肺功能丧失发生在6岁之前，这表明可能对肺发育和结构有直接影响，但发病机制尚不清楚。同样，免疫系统也在同一时期发展。越来越多的数据表明，暴露可以直接影响免疫系统，包括调节性T细胞的发育。本提案的主要目标是检验暴露于DEP和过敏原影响婴儿免疫模式和功能以及肺形态发生增加哮喘和过敏性疾病风险的中心假设。为了解决这一假设，我们将利用遗传操纵的环境暴露和哮喘小鼠模型。目的是确定DEP和空气过敏原暴露对以下方面的影响：1）出生后肺形态发生、结构和功能; 2）调节性T细胞发育和功能、过敏性致敏模式和肺部炎症; 3）CCAAPS中的肺功能、调节性T细胞模式和细胞因子谱。CCAAPS中的所有儿童都量化了他们的DEP暴露以及他们对过敏原的暴露。CCAAPS由NIEHS资助，作为CCAAPS的一部分，儿童将在7岁时进行肺功能测试。DEP赋予风险的机制将在我们的实验模型和从CCAAPS队列收集的样本中进行平行研究。该提案汇集了在肺发育和重塑（Le Cras），儿童哮喘/过敏和免疫调节（Khurana Hershey）以及环境暴露对人类健康（LeMasters）方面具有良好记录的研究人员。公共卫生相关性：哮喘是一个主要的公共卫生问题，患病率持续上升，特别是在儿童中。这项研究将确定暴露于柴油机废气颗粒和过敏原影响婴儿免疫模式和功能以及肺发育的机制，增加哮喘和过敏性疾病的风险。(End摘要）

DESCRIPTION (provided by applicant): Asthma, a chronic inflammatory disorder of the airways, is a major public health concern, especially in children, affecting > 9 million children (13%) in the U.S. alone. Studies point to air pollution, including traffic emissions, as playing a significant role in the development of asthma and expression of asthma symptoms. This current proposal is based on our recent findings in the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS) longitudinal birth cohort demonstrating that diesel exhaust particle (DEP) exposure during infancy conferred risk for wheezing in a dose-dependent fashion. Although the link between DEP exposure and wheezing/asthma outcomes has been reported in many studies, the mechanisms underlying this association remain unclear. Clearly, there is a critical time period in early life when exposures have a significant health outcome. Importantly, during this period, lung development is also occurring. Delineating the mechanisms by which exposure to air pollution and allergens early in life impact the long-term risk for asthma is important as these factors can be controlled. Children with asthma have a more rapid decline in lung function as they age compared to normal individuals and the observed loss in lung function occurs before the age of 6, suggesting that there may be a direct effect on lung development and structure, however the pathogenesis is unclear. Similarly, the immune system is developing over this same time period. There is increasing data that exposures can directly affect the immune system including the development of T regulatory cells. The primary goal of this proposal is to test the central hypothesis that exposure to DEP and allergens impacts immune patterning and function and lung morphogenesis in infants increasing the risk for asthma and allergic disease. In order to address this hypothesis, we will utilize genetically manipulated mouse models of environmental exposures and asthma. Aims will determine the impact of DEP and aeroallergen exposure on: 1) postnatal lung morphogenesis, structure, and function; 2) regulatory T cell development and function, allergic sensitization patterns, and lung inflammation; and 3) lung function, regulatory T cell patterns, and cytokine profiles in CCAAPS. All of the children in CCAAPS have quantified measures of their DEP exposure, as well as their exposures to allergens. CCAAPS is funded by NIEHS, and as part of CCAAPS, the children will have pulmonary function testing performed at age 7. The mechanisms by which DEP confers risk will be investigated in parallel in our experimental models and in samples collected from the CCAAPS cohort. This proposal brings together investigators with a strong track record in lung development and remodeling (Le Cras), childhood asthma/allergy and immune regulation (Khurana Hershey), and environmental exposures on human health (LeMasters). PUBLIC HEALTH RELEVANCE: Asthma is a major public health problem that continues to increase in prevalence, particularly in children. This study will determine mechanisms by which exposure to diesel exhaust particles and allergens impacts immune patterning and function and lung development in infants increasing the risk for asthma and allergic disease. (End of Abstract)