Pathogenesis and Therapeutic Approaches in Primary Ciliary Dyskinesia

OVERALL ABSTRACT/PROJECT SUMMARY Mutations in more than 50 different genes cause Primary Ciliary Dyskinesia (PCD) by disrupting the activity of motile cilia that facilitate mucociliary transport. Knowledge of PCD has come from studies identifying disease- causing mutations, characterizing structural cilia abnormalities, finding genotype-phenotype relationships, and studying the cell biology of cilia. Despite these important findings, we still lack effective treatments and people with PCD have significant pulmonary impairment. As with nearly every other disease, a better understanding of pathogenic mechanisms can lead us to effective treatments. To overcome some of these limitations, we developed a PCD pig with DNAI1 disrupted. PCD pigs develop the hallmark sinonasal and pulmonary features of human PCD including neonatal respiratory distress in newborns and mucus obstruction, inflammation, infection, and bronchiectasis in older pigs. It is already providing exciting discoveries that provide some of the foundation for the central theme of this PPG. The overarching goal of this program is to understand better the pathophysiology of PCD airway disease to improve treatments and preventions that will change the lives of people who suffer from this debilitating disease. The Projects are closely interrelated. We will address 3 main questions: What is the early pathogenesis of PCD? What happens to mitochondrial-dependent metabolism when ciliary beating is impaired? Will DNAI1 gene addition to ciliated epithelial cells repair the outer dynein arm, restore cilia function, and impact disease development and progression? We hope to have an important positive impact on accelerating discovery of new disease mechanisms and therapeutic interventions for PCD.