Identification of Novel Strategies to Correct the Chloride Transport Defect

Cystic fibrosis (CF) is one of the most frequent genetic diseases, characterized by a progressive and irreversible damage of the lungs and the pancreas. CF is caused by mutations that abolish the function of a protein expressed in the epithelial cells of many organs. The affected protein, called CFTR, is needed to transport chloride ions. So far, there are no effective therapies able to cure the CF basic defect and to stop the progression of the disease. Nevertheless, studies carried out on cultured cells have shown that the function of the mutant CFTR protein can be restored by specific chemical compounds. Therefore, these compounds represent promising drugs. Our project is focused on two main objectives. First, we will look for drug-like compounds able to correct the basic defect caused by F508del, the most frequent mutation among CF patients. For this purpose, we will screen a large collection of small molecules using a fast assay performed on cultured cells. Using the same assay, we will screen a collection of small interfering RNAs (siRNA) which have the ability to silence the expression of intracellular genes. This approach will reveal other proteins acting as modulators of the CFTR protein with the F508del mutation. Such proteins may be the target for therapeutic treatments. The second objective is the study of TMEM16A protein, which we have identified recently. TMEM16A is also able to transport chloride ions. Therefore, it has a role that is complementary to that of CFTR. We propose to identify chemical compounds able to stimulate TMEM16A. The pharmacological stimulation of TMEM16A is a promising way to bypass the mutant CFTR protein thus correcting the basic transport defect in CF.