Grant: Project Grant

Cystic fibrosis (CF), the most common genetic disease among Caucasians, 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 in CF patients. Several years ago, we thus decided to devote our efforts to identify novel therapeutic strategies to promote lung repair in CF patients. We first discovered that the capability of airways to repair after injury is less efficient in CF patients 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 correctors significantly enhances airway repair, but this CFTR rescue and repair improvement are dampened by bacteria. Importantly, we have new data supporting that lung repair could be improved by targeting products released by bacteria and using combinations of CFTR modulators. Using both airway cells and bacteria collected from CF patients, our aim is now to dissect the mechanisms whereby CFTR and infection regulate epithelial repair. Then, we will precisely define the bacterial products responsible for the deleterious effect of infection on airway repair and CFTR rescue. Finally, our aim is to evaluate the most effective strategy, with CFTR modulators and compounds interfering with bacteria, to reach the highest level of CFTR rescue and CF airway repair improvement, despite the presence of infection. Our project will allow better understanding of the contribution of the CFTR defect and bacterial infection in the failure of the CF airway to repair after injury. Our data will also give novel insights to predict the efficiency of CFTR correctors in the presence of infection and to define the best strategy to improve lung repair in infected CF patients.