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

描述(由申请人提供)： 哮喘是一种慢性呼吸道炎症性疾病，是一个主要的公共卫生问题，尤其是在儿童中，仅在美国就有900万儿童(13%)受到影响。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现中起着重要作用。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，该发现表明，婴儿时期接触柴油废气颗粒物(DEP)会以剂量依赖的方式增加喘息的风险。尽管在许多研究中已经报道了DEP暴露和喘息/哮喘结果之间的联系，但这种联系背后的机制仍然不清楚。显然，在生命早期有一段关键时期，暴露会对健康产生重大影响。重要的是，在此期间，肺部发育也在发生。描述生命早期暴露于空气污染和过敏原对哮喘长期风险的影响机制是重要的，因为这些因素是可以控制的。与正常儿童相比，哮喘儿童随着年龄的增长，肺功能的下降速度更快，观察到的肺功能丧失发生在6岁之前，这表明这可能对肺的发育和结构有直接影响，但发病机制尚不清楚。同样，免疫系统在同一时间段内也在发育。越来越多的数据表明，暴露会直接影响免疫系统，包括T调节细胞的发育。这项建议的主要目标是检验核心假设，即暴露于DEP和过敏原会影响婴儿的免疫模式和功能以及肺形态发生，增加哮喘和过敏性疾病的风险。为了解决这一假设，我们将利用环境暴露和哮喘的基因操纵小鼠模型。AIMS将确定DEP和空气变应原暴露对以下方面的影响：1)出生后肺的形态发生、结构和功能；2)调节性T细胞的发育和功能、过敏性致敏模式和肺部炎症；以及3)CCAAPS的肺功能、调节性T细胞模式和细胞因子谱。CCAAPS的所有儿童都对他们的DEP暴露以及他们对过敏原的暴露进行了量化测量。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引发风险的机制将在我们的实验模型中和从CCAAPS队列中收集的样本中进行平行调查。这项建议将在肺发育和重塑(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的影响(LeMaster)方面拥有良好记录的研究人员聚集在一起。与公共卫生的相关性：哮喘是一个主要的公共卫生问题，其流行率持续上升，特别是在儿童中。这项研究将确定暴露于柴油废气颗粒物和过敏原对婴儿免疫模式、功能和肺发育的影响机制，增加哮喘和过敏性疾病的风险。(摘要结束)

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)