Grant: Operating Grant

While allergies are very common, affecting ~40% of the population in most Western countries, only a proportion of allergic people develop asthma. This highlights the importance of tissue and cell specific mechanisms that contribute to the disease. In the current proposal we will address how the structure and function of cells that line the airways, called epithelial cells contribute to asthma. As the interface between the inhaled environment and the internal environment of the lung, the epithelium normally possesses numerous mechanisms to maintain an effective protective barrier. However, the inability of the airway epithelium to effectively defend the lung against normally innocuous inhaled agents in asthma strongly suggests that asthma must involve defects in the epithelial barrier rather than being primarily an allergic disease. We believe that in asthma, certain types of epithelial cells do not go through normal stages of development and differentiation and as a consequence, remain "immature". This in turn leads to a chronic cycle of dysregulated damage and repair which ultimately impacts on the airway's function by increasing inflammation, but also by causing changes to the structure of the airway wall in a process called remodeling, which is similar to a non-healing scar on a skin wound. We have evidence that two key molecules which are specifically involved in epithelial cell development and maturation are not well regulated in asthmatic epithelial cells and this may be what is keeping them in an immature state. We will target these molecules in epithelial cells in culture and mouse models of asthma using a compound that is currently in clinical trials for bowel tumors. This application concentrates on a new pathophysiological mechanism of asthma that places the epithelium at the forefront of disease. Epithelial cells are easily reached by inhaled medications in asthma and as such are therapeutically natural targets.