Asthma chronic obstructive pulmonary disease (COPD) and a restrictive spirometry pattern (RSP) are stronglyassociated with increased morbidity and mortality burden. Recent discoveries strongly suggest that the roots ofmany cases of asthma COPD and RSP in adulthood can be found during early life. Prevention of theseheterogeneous conditions for which no cure currently exists requires a thorough understanding of the naturalhistory and mechanistic pathways that underlie their distinct clinical phenotypes. The Tucson Children'sRespiratory Study (TCRS) has already made major contributions to our understanding of the natural history ofasthma and of lung function trajectories and as its participants are entering their fifth decade is now poised toinvestigate prospectively the early risk factors for asthma COPD and RSP as well as the molecular basis oftheir distinct clinical phenotypes. While the origins of atopic asthma (T2) are well established the origins ofnon-T2 asthma which is overrepresented among severe asthmatics and for which no efficacious treatment isavailable are less well known. We recently showed that both high serum insulin and non-atopic rhinitis at theage of six years are strong separate predictors of asthma from childhood up to age 36 years. These findingsoffer exciting new avenues to understand the pathogenesis of non-T2 asthma based on its natural history.Here we propose to use state-of-the-art single-cell epigenetic and gene expression technologies to comparethe cell type distribution in sputum of participants with and without these two early life risk factors. RegardingCOPD our recent findings suggest that at least half of all patients diagnosed with the disease do not showaccelerated lung function decline during adult life suggesting that airflow limitation had its origins in low airwayfunction trajectories starting in childhood. We now propose to use CT imaging to determine the anatomicalfeatures of the persistently low airway function trajectory. In addition we showed that smokers who hadconfirmed lower respiratory tract illnesses due to respiratory syncytial virus (RSV) in early life are at increasedrisk of having chronic respiratory symptoms in the third decade of life. We now propose to use data into thefifth decade of life to ascertain if the RSV-smoking interaction explains why only a minority of smokers developCOPD. Finally we will investigate the hypothesis that major risk factors for RSP are nutritional problems in-utero and during childhood. We will address 3 specific aims: 1. To assess the cellular and molecular endotypesand the continued influence of early life risk factors on phenotypes of asthma from childhood into mid-adult life.2. To assess the continued influence of early life risk factors and the clinical physiological and airwaystructural alterations of incipient early COPD in mid-adult life. 3. To assess the influence of early life risk factorson plethysmography-defined lung restriction in mid-adult life. As the only birth cohort with hundreds of non-selected participants followed from birth into the fifth decade of life the TCRS offers a unique opportunity toinvestigate the potential disease mechanisms for the early origins of asthma COPD and RSP in adult life.