Mucociliary clearance is a key mechanical defense mechanism of human airways. Respiratory mucus traps pathogens entering the airways, and lung cilia propel them outward via their coordinated directional motion. Defective chloride secretion in epithelial cells, caused by loss-of-function of the CFTR channel, is the basic defect in cystic fibrosis (CF). This defect causes airway surface dehydration, impairment of mucociliary clearance (MCC), and mucus accumulation: this condition favors chronic bacterial infection and inflammation with progressive lung damage.
MCC can be corrected with pharmacological agents targeting CFTR. Alternative targets need to be considered to treat patients carrying undruggable CFTR mutations.  In particular, the activity of the TMEM16A chloride channel could potentially compensate for CFTR loss-of-function in CF, but its role as a therapeutic target in CF is controversial. TRPV4 is another ion channel with an important role in the airway epithelium. It is a calcium channel expressed in ciliated cells where it can work as a sensor of mechanical and chemical stimuli that are then transduced to CFTR.
The aim of this project is to clarify the role of TMEM16A and TRPV4 in the airways in order to understand the right approach (activation or inhibition) to restore MCC in CF. Furthermore to elucidate the mechanisms linking TRPV4 to CFTR and to evaluate the efficacy of potentiators of the calcium cascade in restoring MCC.