PROJECT ABSTRACTAsthma and COPD are the most commonly diagnosed chronic lung diseases in the United States. Studies haveshown that asthma is the most important risk factor for COPD that develops through a course of low lung functionfrom school age that tracks into adulthood. However there is a fundamental gap in understanding the basicunderlying mechanisms of this progression. Club cell secretory protein (CC16) has been described for itspotential as a biological marker of lung epithelial cell injury and recent studies by our group concluded that lowcirculating CC16 levels predict impaired lung function growth in childhood and increased risk of asthma or COPDin adult life. In our cohort adults with asthma with low serum CC16 levels and elevated levels of antibodiesagainst M. pneumoniae (Mp) have a striking 8-fold increase in their odds of developing airflow limitation.These studies highlight the critical need for an intact immune system that protects against lung function declineand provide evidence that persistent early life infections may be a previously overlooked link in understandingprogression of asthma into severe asthma with fixed airflow limitation. We developed a mouse model of earlylife exposure to Mp in which WT or CC16 deficient mice are infected pre-weaning and assessed for lung functionin adulthood and found that CC16-/- mice have persistent airway inflammation and a striking >1000% overbaseline airways resistance as compared to WT controls which is likely attributed to inflammation and airwayremodeling. The overall hypothesis is that CC16 plays a protective role during Mp-driven inflammation that isdependent on binding to its newly discovered receptor the integrin VLA-4. The action of CC16 attenuates lunginflammation remodeling and airway hyperresponsiveness. This hypothesis will be tested by pursuing threespecific aims: 1) Determine the impact of CC16 deficiency on pulmonary inflammation remodeling and lungfunction using M. pneumoniae infection mouse models that include comparisons between an early life and adultinfections 2) Determine if the mechanism by which CC16 protects against inflammation remodeling and loss oflung function is dependent on the VLA-4 receptor and 3) Determine the impact of CC16 deficits in associationwith Mp infection on inflammation remodeling factors and lung function using data and samples from multiplehuman longitudinal cohorts. This proposal is innovative in that we have identified a previously unknownreceptor for CC16 adhesion molecule VLA-4 and we employ a novel translational approach to test ourhypothesis using ex vivo studies animal models and human samples from well-characterized local andinternational cohorts. The proposed research is significant in that these findings will describe a new mechanismby which CC16 functions in a protective manner and may be immediately applicable to other pulmonarypathogens. Since CC16 is an informative and predictive biomarker our studies may provide a novel therapeuticapproach for treating individuals with low circulating CC16 in order to prevent lung function decline over time.