PROJECT SUMMARY/ABSTRACT Cystic fibrosis (CF) is an inherited, multisystem disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes the CFTR epithelial anion channel. CFTR works in balance with the epithelial sodium channel (ENaC) to maintain hydration of the airway surface. Perturbations of this system in CF result in dehydrated airway mucus, defective mucociliary clearance, and lung infection that accounts for the majority of CF morbidity and mortality. Recently approved CFTR-modulator drugs have revolutionized the treatment of people with CF who have the most common pathogenic CFTR variants. However, approximately 10% of people with CF have class I CFTR variants, including variants caused by premature termination codons (PTCs), which result in no CFTR mRNA or protein. These people with CF are ineligible for CFTR modulators. There is an unmet need for innovative therapies to treat these individuals. The recently developed thalidomide derivative CC-90009 is a small-molecule drug currently in Phase 1 clinical trials for acute myeloid leukemia. Studies in our lab demonstrated that CC-90009 both rescues class I CFTR PTC variants and unexpectedly also reduces ENaC activity in primary human airway epithelial cells. These promising dual effects are predicted to help restore mucus hydration and improve mucociliary clearance in CF. However, much remains unknown about CC-90009, including whether it restores pathologically decreased PTC- CFTR airway surface layer height and mucus hydration in CF, the mechanism by which it reduces ENaC activity, and its effects in animal models of CF. Given these knowledge gaps, the specific aims for this proposal are to: 1) Interrogate the functional consequences and mechanism of CC-90009’s impact on ENaC activity 2) Evaluate CC-90009’s effects in animal models of CF to gauge its potential translational utility Completing these aims with guidance from my scientific and medical mentors in UNC’s Marsico Lung Institute will provide a rich opportunity to master a suite of innovative basic and translational biomedical research techniques. Collectively, this work will position me for a career as a physician-scientist invested in better understanding respiratory cell biology and disease. The results will also further our understanding of the therapeutic potential of thalidomide-derivative drugs and therapies directed at novel molecular pathways to treat class I CFTR variants, and all people with CF.