Childhood Predictors of Airway Structure, Function, and Disease in Adult Life

描述(申请人提供)：很明显，许多成人疾病的种子都是在童年播下的。当前项目的目标是确定婴儿和儿童慢性成人哮喘、吸烟相关症状、肺功能缺陷和呼吸道结构改变的预测因素，所有这些都与慢性阻塞性肺疾病(COPD)的发展风险相关。具体目标是：1.确定呼吸道症状和哮喘进入生命第四个十年的早期分子、表型和环境预测因子。2.确定进入生命第四十年的肺功能缺陷的早期分子、表型和环境预测因子；3.利用非侵入性成像技术检测表征不同类型的呼吸道功能障碍的结构变化。该项目将利用图森儿童呼吸研究(CRS)，这是第一个未经选择的儿童进入成年生活的大型出生队列，直接调查成人呼吸道疾病的童年起源。CRS受试者的呼吸健康状况从出生到26岁都有广泛的特征，我们有数千份储存的血清样本，每隔5年重复测量一次肺功能，并从出生到26岁期间进行13次调查的问卷调查。在这个庞大的人口样本中，仍有800多名受试者(约占登记人数的2/3)参与其中。在下一个项目期间，我们建议在32岁时评估这些受试者的呼吸状态，那时肺功能的平台期已经结束，与衰老相关的肺功能开始下降。除了肺功能测量和广泛的问卷调查外，还将利用两项新技术进一步阐明成人慢性呼吸道疾病发展的早期根源和生理后果。在此报道的初步研究表明，出生时可识别的血清生物标志物可预测峰值血流变异性增加，以及与哮喘症状相关的肺功能缺陷。因此，我们将检测早期血清中的89种蛋白质，以确定导致后来慢性哮喘和COPD相关气流受限的复杂、相互关联的炎症和免疫过程的生物标志物。螺旋CT扫描将证实气道壁厚度与肺功能和症状的复杂关系的初步发现，并将结构结果与早期生命生物标记物联系起来。阐明导致成人持续呼吸道症状和肺功能缺陷的不同呼吸系统表型和生物标志物模式，将有助于确定预防和早期干预哮喘和COPD的新策略。 公共卫生相关性：这项研究为直接调查成人呼吸道疾病的童年起源提供了第一次机会。30岁出头是评估呼吸健康的关键年龄，因为与衰老相关的肺功能开始下降，出现COPD的第一批临床症状。了解成人呼吸道疾病的儿童起源将确定哮喘和慢性气流受限发生的新机制，并提出干预策略。

DESCRIPTION (provided by applicant): It has become clear that the seeds of many adult diseases are sown in childhood. The objective of the current project is to identify infant and childhood predictors of chronic adult asthma, smoking related symptoms, deficits in lung function, and altered airway structure, all of which are associated with risk for development of chronic obstructive pulmonary disease (COPD). Specific aims are to: 1. Identify the early molecular, phenotypic and environmental predictors of respiratory symptoms and asthma into the fourth decade of life. 2. Identify the early molecular, phenotypic and environmental predictors of lung function deficits into the fourth decade of life, and 3. Utilize noninvasive imaging techniques to detect the structural alterations that characterize distinct patterns of airway dysfunction. This project will utilize the Tucson Children's Respiratory Study (CRS), the first large birth cohort of non-selected children followed into adult life, to investigate directlythe childhood origins of adult airway disease. The respiratory health of CRS subjects has been extensively characterized from birth to age 26, and we have available thousands of stored serum samples, repeated pulmonary function measurements at 5 yr intervals, and questionnaires from 13 surveys between birth and 26 yrs. Over 800 subjects from this large population sample (~2/3s of those enrolled) still participate. In the next project period, we propose to evaluate the respiratory status of these subjects at age 32, when the plateau phase of lung function has ended and aging-associated lung function decline starts. In addition to lung function measurements and extensive questionnaires, two new technologies will be utilized to elucidate further the early roots and physiologic consequences of the development of adult chronic airway disease. Pilot studies reported herein indicate that serum biomarkers identifiable from birth predict increased peak flow variability, and lung function deficits associated with asthma symptoms. Thus we will measure 89 proteins in early sera to identify biomarkers of the complex, interrelated inflammatory and immune processes that lead to later chronic asthma and COPD-related airflow limitation. Helical CT scans will confirm preliminary findings of the complex relation of airway wall thickness to lung function and symptoms, and relate the structural outcomes to early life biomarkers. Elucidating the different respiratory phenotypes and biomarker patterns that lead to persistence of airway symptoms and lung function deficits in adulthood will advance efforts to identify novel strategies for prevention and early intervention i asthma and COPD. PUBLIC HEALTH RELEVANCE: This study provides the first opportunity to investigate directly the childhood origins of adult airway disease. The early 30s is a critical age at which to assess respiratory health, as aging-associated lung function decline begins and the first clinical manifestations of COPD appear. Understanding the childhood origins of adult airway disease will identify novel mechanisms underlying the development of asthma and chronic airflow limitation, and suggest strategies for intervention.