An increasing number of evidences suggests that pulmonary inflammatory process can enhance the degradation of F508del- CFTR, the protein that is mutated and is the cause of disease in most CF patients. This enhanced degradation leads to worsening of the disease. This project is aimed at verifying that the inflammation process enhances the degradation of F508del-CFTR and reduces the level of the CFTR protein, also compromising the effectiveness of newly approved drugs that target the mutated protein and require its presence to act. Researchers propose: 1) to delineate signaling pathways activated by inflammatory processes that enhance the degradation of F508del-CFTR; 2) to target these pathways using small molecules to overcome the degradation of F508del-CFTR and increase its level. This will then allow more effective rescue of F508del-CFTR by approved drugs. Epithelial cells from the lungs of patients, clinically approved drugs and other standard laboratory reagents will be used. F508del-CFTR degradation and function will be monitored by biochemical methods and functional chloride conductance assays. Inflammatory processes and activation of signaling pathways will be monitored by biochemical and molecular biology methods. The final aim is to explore the way of intracellular inflammatory mechanisms to discover new molecoles improving the efficacy of CFTR-F508del existing modulators.