Grant: Project Grant

Cystic fibrosis (CF), the most common fatal genetic disease in Canada, is due to mutations in the gene coding for a protein called CFTR. Although CF affects many organs, the progressive lung damage due to bacterial infections remains the first cause of mortality. Several years ago, we thus decided to devote our efforts to identify novel therapeutic strategies to promote CF lung repair. We first discovered that the capability of CF airways to repair after injury is less efficient than in healthy subjects, due to both the CFTR dysfunction and the presence of infections. Our work also unveiled that CFTR rescue with new compounds called modulators (potentiator/correctors) significantly enhances airway repair, but CFTR rescue and repair improvement are dampened by the bacterial infectious environment. Importantly, we identified new avenues to counteract the deleterious effect of infection on CFTR rescue and airway repair. Moreover, we have new data supporting that lung repair could be improved with treatments targeting bacterial virulence and combining CFTR modulators with activators of another class of ion channels (i.e. potassium (K+) channels). Using airway epithelial cells collected from CF patients, our first aim is now to dissect how CFTR rescue regulates airway epithelial repair processes. Then, we will investigate new avenues interfering with virulence factors from the main pathogens found in lungs from CF children and adults, i.e. S. aureus and P. aeruginosa, in order to enhance the efficiency of CFTR modulators in infectious conditions. Finally, our aim is to identify the most effective strategies with CFTR modulators, K+ channel activators and compounds interfering with bacteria, to improve the repair of damaged lung tissues from infected CF patients harboring various types of mutations. Our project will give important insights paving the way to innovative strategies for improved CFTR-targeted treatments and restoration of lung integrity.