Project 1

PROJECT 1 PROJECT SUMMARY Primary ciliary dyskinesia (PCD) is an autosomal recessive disease caused by mutations in the genes that encode cilia structural proteins. Mutations in the DNAI1 gene are common in people with PCD and characterized by loss of the outer dynein arm (ODA) of the ciliary central apparatus and loss of ciliary beating. The basic physiological defect in PCD is loss of cilia function, yet the clinical presentation is heterogeneous and includes neonatal respiratory distress, recurrent respiratory tract infections (rhinosinusitis, otitis media, pneumonia, and bronchitis), bronchiectasis, respiratory failure, infertility, and laterality defects. We generated a pig model of PCD that recapitulates the key features of human PCD disease. These pigs develop neonatal respiratory distress, early sinus abnormalities (mucosal thickening and mucus impaction) and early airway abnormalities (air trapping, lobar collapse, and mucus plugging). With time they develop infection, inflammation and remodeling of the airways. Most importantly, they do not develop neonatal lethal hydrocephalus and survive the neonatal stage which allow us to study for the first time the pathogenesis of early PCD disease and the progression of the disease with time. The overall goal of this Project is to better understand the pathogenesis of early lung disease in PCD. We will investigate the viscoelastic properties of PCD mucus, and how its unique characteristics may be an asset for effective cough. We will investigate how small airways are cleared in the absence of functional cilia. We will investigate the progression of mucus obstruction, inflammation, and infection in the lungs, and upper airway sinuses. The results of this Project may lead to novel therapeutic interventions for people with PCD and other airway diseases.