Grant: Operating Grant

The cystic fibrosis (CF) protein (CFTR) resides at the cell surface and ensures normal water and ion content of the liquid that lines the airway surface. The most common mutation in cystic fibrosis impairs the structure and function of CFTR and alters the composition of the airway surface liquid layer. This leads to recurrent lung infection and inflammation, the primary cause of mortality in CF. Despite intensive efforts no cure of the basic defect of the most common CFTR mutant has been identified. We propose to implement novel cell based models to identify novel drug-like molecules and improve the efficacy of the available ones in correcting the molecular defects of the most common CFTR mutation. We also propose means to stabilize the mutant at the cell surface to improve its residual function. Finally, as a complementary approach, we propose to alleviate the cellular consequences and, thereby, the clinical manifestations of CF lung disease by limiting the hyperactive airway inflammation. The proposed, multifaceted approaches will help to identify new therapeutic interventions in this lethal, genetic disease.