Various compounds have been identified that correct the most frequent CF basic defect, CFTR-DF508 mutation. Most of these compounds were identified by random screening procedures and their mechanism of action is not known, limiting our ability to improve them. We propose to develop a rational basis for the pharmacological correction of DF-CFTR defects, by characterizing the mechanism of action of correctors, to identify molecular components and pathways involved in the correction and then targeting them by efficient ways. The results will also be validated using primary human bronchial epithelial cells and CF mouse models.