Lung disease is the major cause of morbidity and mortality in cystic fibrosis (CF), a devastating disease that afflicts ~30,000 individuals in the U and ~70,000 worldwide. Life expectancy for individuals with CF is currently 38 years. Lung function typically begins to decline during the teenage years and lung disease sets in between 20-30 years of age. Cycles of bacterial infection, inflammation, and airway obstruction precipitate lung disease. CF is caused by mutation of a single gene: cystic fibrosis transmembrane conductance regulator (CFTR). CFTR dysfunction contributes to airway inflammation, which is present even in uninfected CF infants and is excessive for bacterial loads in infected patients. CF airway epithelial cells contribute to excessive inflammation via increased pro-inflammatory signaling. Prior airway epithelial cell models for CF are not ideal for one of two reasons. First, some disease models do not have genetically matched controls. Genetic matching is important because CF lung disease severity is altered by dozens of single nucleotide polymorphisms located throughout the genome. Second, some disease models have been manipulated by heterologous expression of functional CFTR or interference with CFTR. While these models have proved useful, they do not address questions that involve endogenous CFTR regulation. This project will utilize a novel cell model: gene-edited primary human airway epithelial cells with genetically matched disease/control cells and endogenous CFTR regulation. Increased inflammatory signaling in CF airway epithelial cells correlates with epigenetic alterations and decreased levels of the epigenome-altering protein histone deacetylase 2 (HDAC2). This proposal explores pathways leading to decreased HDAC2 levels. One such pathway is targeted to treat non-CF lung diseases such as chronic obstructive pulmonary disorder (COPD). If commonalities are uncovered, then treatments available for COPD may be useful for CF. Reducing airway inflammation in pediatric patients would forestall development of lung disease and improve patient quality of life. Ivacaftor, a drug that directly addresses CFTR dysfunction, was recently approved for treatment of CF in a minority of patients. The mechanistic links between Ivacaftor and improved lung health remain unstudied at the basic science level. This proposal explores airway epithelial cell inflammatory response to Ivacaftor treatment. Results will inform clinical expectations for inflammatory resolution and the potential utility of co-treatment with anti-inflammatory drugs.
The airway epithelial cells of patients with cystic fibrosis release excessive inflammatory signals that help precipitate lung disease. This proposal will elucidate mechanisms behind excessive inflammatory signaling as well as the potential for clinical reversibility.
