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

生命早期接触柴油对免疫模式和肺结构/功能的影响

基本信息

批准号：
7924049
负责人：
Gurjit K. Khurana Hershey
金额：
$ 52.31万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7924049
关键词：
7 year old Address Adolescent Adult Advisory Committees Affect Age Air Pollutants Air Pollution Allergens Allergic Allergic Disease Alveolar Animal Model Asthma Atopic Dermatitis Birth Blood specimen Child Childhood Childhood Asthma Chronic Chronic Disease Cohort Studies Cotinine Data Development Diesel Exhaust Disease Dominant-Negative Mutation Dose Dust Elastin Environmental Exposure Epidermal Growth Factor Receptor Epithelial Experimental Models Exposure to Fibrosis Funding GSTP1 gene Gender Goals Growth Growth Factor Hair Health Home environment Human Hypersensitivity IgE Immune Immune system Immunoglobulin G In Vitro Individual Infant Inflammation Inflammatory Inflammatory Response Institution Kinetics Life Link Longitudinal Studies Lung Lung Inflammation Measurement Measures Mechanics Mediator of activation protein Morphogenesis Mus Mutant Strains Mice National Institute of Environmental Health Sciences Neonatal Nicotine Outcome Oxidative Stress Parents Particulate Matter Pathogenesis Pathway interactions Pattern Phase Phenotype Physicians Play Pollution Prevalence Production Public Health Pulmonary Function Test/Forced Expiratory Volume 1 Pulmonary function tests Pyroglyphidae Race Regulation Regulatory T-Lymphocyte Reporting Research Personnel Respiratory physiology Rhinitis Risk Role Sampling Signal Transduction Structure Symptoms T-Cell Development T-Lymphocyte Testing Time Transgenic Organisms Venipunctures Wheezing abstracting air cleaner airborne allergen airway goblet cell hyperplasia airway inflammation base chemokine cohort cytokine early childhood infancy lung development methacholine mouse model neonate particle particle exposure peripheral blood population based postnatal public health relevance response skin hypersensitivity trafficking

项目摘要

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)

描述（由申请人提供）：哮喘是一种慢性气道炎症性疾病，是一个主要的公共卫生问题，尤其是儿童，仅在美国就有超过 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发挥着重要作用。目前的提议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，该研究结果表明，婴儿期柴油机尾气颗粒 (DEP) 暴露会以剂量依赖性方式带来喘息风险。尽管许多研究报告了 DEP 暴露与喘息/哮喘结果之间的联系，但这种关联的机制仍不清楚。显然，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，肺部也在发育。描述生命早期接触空气污染和过敏原影响哮喘长期风险的机制非常重要，因为这些因素是可以控制的。与正常人相比，患有哮喘的儿童随着年龄的增长，肺功能下降得更快，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，但发病机制是不清楚。同样，免疫系统也在同一时期发育。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。该提案的主要目标是检验以下中心假设：接触 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，从而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。目标将确定 DEP 和气源性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 中的所有儿童都对他们的 DEP 暴露以及过敏原暴露进行了量化测量。 CCAAPS 由 NIEHS 资助，作为 CCAAPS 的一部分，孩子们将在 7 岁时进行肺功能测试。DEP 带来风险的机制将在我们的实验模型和从 CCAAPS 队列中收集的样本中并行研究。该提案汇集了在肺部发育和重塑（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）方面拥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，尤其是在儿童中。这项研究将确定接触柴油机尾气颗粒和过敏原影响婴儿免疫模式和功能以及肺部发育从而增加哮喘和过敏性疾病风险的机制。（摘要完）