PROJECT SUMMARY The airway system is composed of asymmetric dichotomously branching tubes lined with respiratory epithelium that form a barrier at the interface with the environment. The airways carry a simple function of conducting oxygen rich air to the alveolar space where gas exchange with the blood occur. By doing that, pathogens and particles enter the lungs. Mucociliary transport is a host defense mechanism that protect the lungs from invading organisms. Defects in mucociliary transport contributes to many airway diseases such as asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, cystic fibrosis, and primary ciliary dyskinesia. We developed limited understanding of the mechanism of MCT in large airways by investigating the role of submucosal gland secretions. We found that mucus strands secreted by submucosal glands are critical to initiate movement of large particles in large airways. We also found that in CF airways, due to loss of CFTR-mediated anion secretion, mucus strands are abnormally elastic. They fail to detach from submucosal gland duct opening and often recoil backward while transporting on the airway surface. Small airways constitute the majority of the surface airway of the lungs and it is suggested that may contribute to some of the abnormalities seen in several airway diseases. The hypothesis that mucociliary defects in small airways contribute to CF airway disease pathogenesis has largely remained untested. In addition, the characteristic features of MCT in small airways has remained poorly understood. To understand mucociliary transport in the small airways, we developed a positron emission based mucociliary transport assay with high spatial and temporal resolution not achieved before. We used CF airway disease as a disease model of impaired mucociliary transport. To realize our overarching goal of understanding the mechanism of mucociliary transport in both small and large airways, we will test hypotheses in the f