PROJECT ABSTRACTPersistence of childhood asthma into adult life has been conclusively linked to long-term lung function deficitsand an increased susceptibility to non-fully reversible airflow limitation the hallmark of chronic obstructivepulmonary disease. Yet at the present time there are neither established prediction models nor availablebiomarkers for early risk identification of long-term sequelae in childhood asthma. In preliminary studies wefound early levels of circulating CC16 a pneumoprotein that is produced mainly by club cells in the distalairways and can be measured in circulation to be associated with resilience to subsequent lung functiondeficits and persistent asthma. Of note these effects were independent of known risk factors for persistentdisease. In addition we found CC16-/- mice to have lung function deficits airway alterations and susceptibilityto infections by Mycoplasma pneumoniae as compared with wild-type animals. These findings support CC16 inearly school age as a strong and independent factor for resilience to persistent disease and long-termsequelae in children with asthma and suggest that CC16 may exert these effects by modulating susceptibilityand responses to airway infections. The present proposal addresses 1) the identification of early determinantsof circulating CC16 levels by school-age; 2) the value of levels and trajectories of circulating CC16 in childhoodas predictors of persistence and severity of asthma into adult life; and 3) the evaluation of airway responses toasthma pathogens as a potential mechanism mediating CC16 effects on persistent disease.