Early Origins of Chronic Lung Disease: From Birth to Age 45 Years

University Of Arizona, Tucson AZ

Investigators

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Abstract

PROJECT SUMMARY: Asthma, chronic obstructive pulmonary disease (COPD) and the Preserved ratio impaired spirometry (PRISm) are associated with increased morbidity and mortality across the lifespan. Recent discoveries strongly suggest that the roots of many cases of these three heterogeneous conditions can be found in early life. Identifying the lifetime molecular pathways underlying them will provide a new understanding of the pathogenic mechanisms involved in their inception. The Tucson Children’s Respiratory Study (TCRS) is a birth cohort that has already made major contributions to our understanding of the natural history of lung function trajectories and the early origins of asthma and COPD. A recent tantalizing result was derived from the use of lung function measurements obtained repeatedly from early childhood through the beginning of the 5th decade of life to model latent class trajectories in over 600 participants. We identified a novel resilient trajectory, in which lung function decline occurs at a slower rate than in their peers. Early data suggests that this resilience may be afforded through increased lung protective antiproteases molecules. We also identified individuals with dysanapsis, i.e., disproportionate scaling of airway dimensions to lung volume, which is a risk factor for COPD. A strong precursor of dysanapsis was excessive weight gain between infancy and the early school years and we found a specific serum biomarker at age 6, PTX2, that may mediate this association. We showed that restrictive spirometry is associated with poor prenatal and early life growth and detected early life developmental modules that may be responsible for these differences. We identified phenotypes related to the natural history of asthma, and linked these to novel metabolic pathways that may be responsible for the onset or persistence of asthma. TCRS participants are in the 5th decade of life, when lung function changes associated with chronic lung disease become increasingly more apparent. In this application, we have adapted new technologies, such as gold standard metabolomics, proteomics, and single-cell and bulk RNA sequencing, applied to longitudinally collected samples, in combination with ongoing assessment of the participants. Using these technologies, we will investigate, prospectively, the early risk factors for these lung disorders at the molecular level. We will address three specific aims: 1. To continue following TCRS participants to further characterize different lung function trajectories and phenotypes from childhood into adult life, and to specifically assess the molecular underpinnings of lung dysanapsis and of the obstructed and resilient trajectories. 2. To identify profiles in the serum proteome and peripheral blood gene expression patterns associated with poor postnatal somatic growth, and to relate these profiles to the restricted spirometric trajectory. 3. To characterize the novel cellular and molecular mechanisms underlying the natural history of asthma. 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 to investigate the longitudinal mechanisms underlying these lung disorders.