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：
8107575
负责人：
Gurjit K. Khurana Hershey
金额：
$ 51.57万
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/8107575
关键词：
7 year old Address Adolescent Adult Advisory Committees Affect Age Air Air Pollutants Air Pollution Allergens Allergic Allergic Disease Allergic rhinitis 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 Risk Role Sampling Signal Transduction Structure Symptoms T-Cell Development T-Lymphocyte Testing Time Transgenic Organisms Venipunctures Wheezing abstracting 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 response skin prick test 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，尤其是在儿童中，仅在美国就影响了900万儿童（13％）。研究指出，空气污染，包括交通排放，是在哮喘的发展和哮喘症状表达中发挥重要作用。当前的建议基于我们在辛辛那提儿童过敏和空气污染研究（CCAAPS）纵向出生队列中的最新发现，表明婴儿期在婴儿期赋予剂量依赖性喘息风险的风险中暴露。尽管在许多研究中已经报道了DEP暴露与喘息/哮喘结局之间的联系，但该关联的基础机制尚不清楚。显然，在早期生活中有一个关键的时期，暴露有很大的健康结果。重要的是，在此期间，肺发育也发生。描绘出生命早期暴露于空气污染和过敏原的机制会影响哮喘的长期风险，因为可以控制这些因素。与正常个体相比，哮喘儿童随着年龄的年龄的年龄增长，肺功能的迅速下降，并且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，但是发病机理是不清楚。同样，免疫系统也在同一时期发展。越来越多的数据表明，暴露会直接影响免疫系统，包括调节细胞的发展。该提案的主要目的是检验中心假设，即暴露于DEP和过敏原会影响婴儿的免疫模式，功能以及肺形态发生，从而增加了患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遗传操纵小鼠模型。 AIMS将确定DEP和AeroalerRegen暴露对以下原因的影响：1）产后肺形态发生，结构和功能； 2）调节性T细胞发育和功能，过敏敏化模式和肺部炎症； 3）CCAAP中的肺功能，调节性T细胞模式和细胞因子谱。 CCAAP中的所有儿童均已量化其DEP暴露的度量，以及对过敏原的暴露。 CCAAP由NIEHS资助，作为CCAAP的一部分，儿童将在7岁时进行肺功能测试。在我们的实验模型中以及从CCAAPS队列中收集的样品中，DEP赋予风险的机制将同时研究。该提案将研究人员汇集到肺发育和改造（LE CRA），童年哮喘/过敏和免疫调节（Khurana Hershey）以及人类健康（Lemasters）的环境暴露（Lemasters）方面具有良好的记录。公共卫生相关性：哮喘是一个主要的公共卫生问题，它继续增加患病率，尤其是在儿童中。这项研究将确定暴露于柴油排气颗粒和过敏原的机制会影响婴儿的免疫模式和功能以及肺发育，从而增加了哮喘和过敏性疾病的风险。（抽象的结尾）