Grant: Project Grant

The cystic fibrosis (CF) protein (CFTR) resides at the cell surface and ensures normal water and ion content of the airway surface liquid layer. Disease causing mutations in CF impair the structure and function of CFTR and alter the composition of the airway surface liquid layer. This leads to recurrent lung infection and uncontrolled inflammation, the primary cause of mortality in CF. Although effective drug combinations have been recently identified to rescue the basic defects of the most common mutants (folding and gating mutants), the long-term decay of the CF lung function can only be delayed but not prevented by available drugs. Other mutations either have not been tested, remained partially or fully therapy resistant towards the presently available drugs. Furthermore, a unique class of mutations, represented by "premature termination codons", which introduce and early termination signal for protein synthesis, manifests in variable truncation of CFTR. We propose a variety of biochemical, biophysical and cellular assay to a) unravel the molecular bases of those mutations that mechanism is presently not known, b) deepen our understanding of the channel opening mechanism, a prerequisite stimulate this process for mutants that lead to functional defect and c) identify the binding sites of the available gating and folding correctors drugs, the foundation for rationally improving their efficacy. Finally, we propose innovative experiments to rescue the functional expression defect of premature truncation mutants that presently lack any therapy. Our program with interdependent basic and translational components will help to identify improve therapeutic interventions in CF and may serve as a framework for other genetic diseases caused by mutations in ABC transporter family.