Even after rescue to the plasma membrane, F508delCFTR demonstrates defects in gating and residence time, thus a corrector – potentiator combination therapy to rescue F508delCFTR and increase protein function is presently recommended. Recently, two independent research groups demonstrated that long-term effects of some potentiators reduce the plasma membrane stability of corrected F508del CFTR protein. The researchers of this project deepened the question and observed that the potentiator VX-770 induces a reduction of both ezrin phosphorylation and a reorganization of membrane lipids in CF cells, suggesting a possible involvement of sphingolipids (SLs) on CFTR plasma membrane stability. Therefore they hypothized that some potentiators could alter the SL reorganization. The aim of the present project is to identify SL modulators effective to reduce the negative effect of gating potentiators on the CFTR function.