Early Life Predictors of Airway to Lung Dysanapsis

PROJECT SUMMARY/ABSTRACT Chronic obstructive pulmonary disease (COPD) accounts for 6% of all deaths worldwide and is potentially preventable, with well-described but poorly elucidated childhood origins. Our research team recently identified that the mismatch between airway tree caliber and lung volume that arises early in life, dysanapsis, is: 1) prevalent among older adults when measured by computed tomography (CT), 2) is a major predictor of COPD risk – exceeding tobacco smoke and other established risk factors, and 3) is not fully explained by genetics. We also know that there are heterogenous structural presentations of dysanapsis. Variation in dysanapsis, and COPD risk, may have early life, environmental causes. Research has revealed that two early risk factors, obesity and viral respiratory infections, contribute to two distinct subtypes of dysanapsis that have yet to be examined. Several studies have also examined the impact of early-life air pollution exposure on lung function and growth, with limited generalizability due to the use of racially/ethnically homogenous populations and not accounting for neighborhood-level social factors as effect modifiers. This R01 study will leverage 8 longitudinal birth cohorts of diverse children to examine the relationship between early-life exposures and both the structural (imaging-assessed) and functional (spirometry- assessed) determinants of dysanapsis throughout childhood and adolescence to identify modifiable risk factors and help reduce risk of COPD in future generations at risk. Building on our preliminary data showing that magnetic resonance imaging (MRI) is as accurate as CT at identifying dysanapsis, we will integrate state- of-the-art lung MRI data with extensive early-life exposure and lung function data. Aim 1 will establish relationships between early life dysanapsis (functionally-confirmed) and childhood lung function trajectories, and their relationship to dysanapsis (functionally- and structurally-confirmed) at late adolescence. Aim 2 will determine if obesity and viral infections contribute to distinct structural subtypes of dysanapsis (structurally- confirmed). Aim 3 will examine early life air pollution exposures and neighborhood social factors association with dysanapsis (functionally-confirmed) in diverse cohorts of children. This study aligns with NHLBI's strategic objective to investigate factors accounting for health differences among populations. We will establish the early life risk factors that contribute to airway-to-lung phenotypes and enhance our understanding of the utility of both structural- and functional-based measures of dysanapsis. Ultimately, our findings will inform targeted interventions to high-risk groups of children to reduce their subsequent risk of COPD.