Early Origins of Chronic Airflow Limitation: Outcomes Into the 4th Decade of Life

慢性气流受限的早期起源：生命第四个十年的结果

基本信息

批准号：
9455772
负责人：
Stefano Guerra
金额：
$ 137.64万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9455772
关键词：
Address Adult Adult asthma Affect Age Age-Years American Asthma Biogenesis Birth Breast Feeding Cause of Death Cells Child Childhood Childhood Asthma Chronic Chronic Bronchitis Chronic Obstructive Airway Disease Clinical Cohort Studies Country Data Development Diagnosis Disease Enrollment Environmental Risk Factor Epithelial Cells Event Exposure to Gene Expression Gene Expression Profile Health Care Costs Hospitalization Human In Vitro Infection Integration Host Factors Life Longitudinal Studies Molecular Morbidity - disease rate Natural History Newborn Infant Nose Nursery Schools Outcome Participant Pathway interactions Patients Peripheral Blood Mononuclear Cell Persons Phase Phenotype Plant Roots Pneumonia Population Predisposing Factor Prevention strategy Primary Prevention Recording of previous events Respiratory physiology Respiratory syncytial virus Rhinovirus Risk Risk Factors Role Smoke Smoker Smoking Sputum Symptoms Testing Tissue-Specific Gene Expression Wheezing age related airway obstruction clinically significant cohort early childhood early life exposure mortality pre-clinical prospective public health priorities public health relevance respiratory respiratory virus response

项目摘要

DESCRIPTION (provided by applicant): Asthma and (COPD) are major causes of morbidity and mortality worldwide. The development of primary prevention strategies is thus a major public health priority. Recent findings from the Tucson Children's Respiratory Study (TCRS) and other birth cohorts have shown that most asthma in adults begins in childhood. These cohorts have also identified a specific adult asthma phenotype which is initiated by early lower respiratory illnesses (LRIs) associated with respiratory syncytial virus (RSV) or human rhinovirus (HRV) and that subsequently progresses into both persistent wheezing in childhood and airflow limitation in adult life. Although COPD is commonly considered a disease of rapid decline in lung function associated with smoking, recent studies have shown that up to half of all patients with COPD do not show this rapid decline but rather, start adult life with mild/moderate airway obstruction which, with age-related decline in lung function, results in clinically significnt airflow limitation. We have shown that post-neonatal lung function, episodes of pneumonia by age 3, and severe childhood asthma are major risk factors for diminished maximally attained lung function in the third decade of life. Taken together, these data strongly suggest that the roots of a significant proportion of cases of asthma and COPD in adult life can be found during early life. The objective of this application is to perform functional, clinical, and molecular assessments in TCRS participants at 36-40 years of age to identify the mechanisms that connect early life events with the preclinical phase for the two major subtypes of COPD described above. Concomitantly, we will continue to assess the factors that determine persistence of childhood asthma into adult life. We hypothesize that abnormal responses to respiratory viruses may be major contributors to the early origins of asthma and COPD. The TCRS cohort provides a unique vehicle through which we can now address 3 specific aims: 1.To identify host and environmental factors in early life that predict lung function deficits, persistence of asthma, and development of airflow limitation in mid-adult life; 2. To determine the role of RSV LRI in early life and its interaction with active smoking as determinants of lung function deficits, and to characterize associated alterations in gene expression in induced sputum cells and in PBMCs exposed to RSV. 3. To determine the molecular endotype generated in nasal epithelial cells in response to rhinovirus infection that distinguishes subjects with adult asthma and a history of persistent wheezing in early life from those with adult asthma but without such history. As the only birth cohort that has followed a large number of nonselected subjects into the 4th decade of life, the TCRS offers a unique opportunity to investigate the early life risk factors for and the potential disease mechanisms involved in the origin of asthma and COPD in adult life.

描述（由申请人提供）：哮喘和慢性阻塞性肺病 (COPD) 是全世界发病和死亡的主要原因，因此，图森儿童呼吸系统研究 (TCRS) 和其他出生队列的最新发现表明，制定初级预防策略是一项重要的公共卫生优先事项。研究表明，大多数成人哮喘始于儿童期，这些队列还确定了一种特定的成人哮喘表型，该表型是由与呼吸道合胞病毒（RSV）或人类相关的早期下呼吸道疾病（LRI）引发的。尽管慢性阻塞性肺病通常被认为是一种与吸烟相关的肺功能迅速下降的疾病，但最近的研究表明，多达一半的患者患有鼻病毒（HRV），并随后发展为儿童时期的持续性喘息和成年后的气流受限。慢性阻塞性肺病并没有表现出这种快速下降，而是以轻度/中度气道阻塞开始成年生活，随着年龄相关的肺功能下降，导致临床上显着的气流受限，我们已经表明，新生儿后肺功能，肺炎发作。经过3 岁和严重的儿童哮喘是 30 岁后最大肺功能严重下降的主要危险因素。总而言之，这些数据表明，成人生活中很大一部分哮喘和慢性阻塞性肺病病例的根源是可以找到的。该应用程序的目的是对 36-40 岁的 TCRS 参与者进行功能、临床和分子评估，以确定将早期生活事件与所述两种主要 COPD 亚型的临床前阶段联系起来的机制。与此同时，我们将继续评估决定儿童哮喘持续到成年的因素，我们发现对呼吸道病毒的异常反应可能是哮喘和慢性阻塞性肺病早期起源的主要原因。我们现在可以实现 3 个具体目标： 1. 确定早期生命中预测肺功能缺陷、哮喘持续性和中年时期气流受限发展的宿主和环境因素； 2. 确定 RSV LRI 的作用；早在生活及其与主动吸烟的相互作用作为肺功能缺陷的决定因素，并表征诱导痰细胞和暴露于 RSV 的 PBMC 中基因表达的相关变化。 3. 确定鼻上皮细胞响应鼻病毒感染而产生的分子内型。区分主题的患有成人哮喘并且有成人哮喘但没有这种病史的人在早期有持续性喘息史。作为唯一一个跟踪大量未经选择的受试者到 40 岁的出生队列，TCRS 提供了一个独特的机会。研究成年后哮喘和慢性阻塞性肺病起源的早期危险因素和潜在疾病机制。