PROJECT SUMMARY/ABSTRACT Bronchopulmonary dysplasia (BPD) in preterm infants is a common and often severe lung disease with long term sequelae. Rates of BPD vary between racial/ethnic groups, which may be due to differences in genetic ancestry or environment factors. Changes in the biochemical composition of biofluids (the metabolome) reflect the sum of both genetics and the environment, and thus characterizing these changes offers a broader view of the disease process as compared to genetic studies alone. Our goal is to increase our understanding of the biological basis of BPD and response to interventions in genetically diverse preterm infants at high risk of dis- ease. We hypothesize that there are temporal changes in the urinary and tracheal aspirate (TA) metabolome of the premature infant that are associated with respiratory outcomes and interventions, and that some of these changes vary by infant genetic ancestry. We will test our hypothesis with three specific aims. Specific Aim 1: Longitudinal characterization of the urinary and lung fluid metabolome of preterm infants. We will measure longitudinal changes in metabolic profiles of urine and tracheal aspirates in two cohorts of preterm infants at high risk of BPD from three racial/ethnic groups. We will identify changes in the metabolome of infants that are associated with respiratory status (diagnosis of BPD and later respiratory outcomes) and inter- ventions (e.g. type of nutrition, iNO therapy, corticosteroids, and other medications). Results from this aim will provide new information on the biofluid metabolome of preterm infants, biomarkers of disease and response to interventions, and insight into postnatal lung development and disease pathogenesis. Specific Aim 2: Examine the contribution of genetic ancestry, race and ethnicity on longitudinal changes in the biofluid metabolome of preterm infants. We will investigate the contribution of genetic ancestry and maternal self- reported race/ethnicity on temporal changes in the biofluid metabolome of premature infants. We will identify metabolites and pathways whose trajectories are associated with genomic ancestry independent of maternal race/ethnicity, and identify those under stronger genetic vs. social/ environmental determination. Results from this aim will provide new information as to the role of genetics on the biofluid metabolome of preterm infants as it relates to racial/ethnic differences in BPD and response to interventions. Specific Aim 3: Integrate genomic and metabolomic studies of BPD. We will identify novel metabolite quantitative trait loci (mQTL) in high risk preterm infants using a two-step approach that leverages variation in local genetic ancestry, and develop a resource to empower multi-omic studies of BPD. We will then combine this information with a genome-wide association study (GWAS) of BPD by integrating metabolomic and genomic associations in the same infants to identify novel genetic loci and biochemical pathw...