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（由适用提供）：哮喘和（COPD）是全球发病率和死亡率的主要原因。因此，制定初级预防策略是一个主要的公共卫生优先事项。图森儿童呼吸研究（TCRS）和其他出生队列的最新发现表明，成年人的大多数哮喘都始于童年。这些队列还确定了特定的成年哮喘表型，该表型是由早期的下呼吸道疾病（LRIS）引发的，与呼吸道合胞病毒（RSV）或人类鼻病毒（HRV）相关，随后在成年人生活中均持续发展为童年和气流限制。尽管COPD通常被认为是与吸烟相关的肺功能快速下降的疾病，但最近的研究表明，所有COPD患者中，多达一半的COPD并没有显示出这种快速下降，而是以轻度/中度气道反对意见开始成人生活，随着年龄相关的肺功能下降，随着年龄相关的肺部功能下降，导致临床上的气流限制。我们已经表明，肿瘤后的肺功能，到3岁时的肺炎发作以及严重的童年哮喘是生命三十年中最大肺功能减少的主要危险因素。综上所述，这些数据强烈表明，在早期生命中可以找到成人生活中相当一部分哮喘和COPD病例的根源。该应用的目的是在36-40岁的TCRS参与者中执行功能，临床和分子评估，以确定上述COPD的两个主要亚型的早期生活事件与临床前阶段联系起来的机制。同时，我们将继续评估确定儿童哮喘持续性成人生活的因素。我们假设对呼吸道病毒的异常反应可能是哮喘和COPD早期起源的主要因素。 TCRS队列提供了一种独特的工具，我们现在可以通过该工具来解决3个具体目标：1。在早期生活中确定宿主和环境因素，以预测肺功能定义，哮喘的持久性以及中期生活中气流限制的发展； 2.确定RSV LRI在早期生命中的作用及其与主动吸烟作为肺功能缺陷的决定剂的相互作用，并表征诱导的痰细胞和暴露于RSV的PBMC中基因表达的相关改变。 3。确定响应于鼻上皮病毒感染的分子内型，以区分受试者有成年哮喘和持续的持续往返历史，但患有成年哮喘的人，但没有这样的历史。作为唯一遵循大量非选择受试者到生命的第四个十年中的唯一出生队列，TCRS提供了一个独特的机会，可以调查成人生活中哮喘和COPD起源的早期生命危险因素以及潜在的疾病机制。