The development of asthma is not well understood — currently, there is no cure, despite the large number of sufferers worldwide. Current therapies successfully control mild asthma, but therapies for patients with severe asthma can be limited in effectiveness.
Historically, asthma was assumed to result from excessive and aberrant inflammation, but clinical observations have demonstrated that severe asthma can persist in the absence of inflammation. Additionally, asthmatic symptoms can appear before inflammation is even detected. Asthmatic patients have consistently been shown to have stiffer airways, with the magnitude of stiffness being directly correlated with asthma severity. Despite these considerations, no stiffness-induced signaling pathways have been implicated in asthma. Similar pathways have been discovered in at least several other diseases, which include breast cancer, pulmonary fibrosis and glaucoma.
In this project, I endeavor to discover and investigate stiffness-induced signaling pathways within airway epithelial cells, which line the airways. To accomplish this, I propose to use both cell culture and mouse models. For my culture studies, I will use two immortalized human airway epithelial cell lines and culture them on hydrogel-coated membrane inserts at an air-liquid interface, which approximates physiological conditions. To alter substratum stiffness, I will modulate the hydrogels' Young's moduli. For my
in vivo studies, I will use well-established, allergen-based mouse models of asthma. I plan to mechanically characterize mouse lungs by generating pressure-volume curves using a custom-built device. In addition, I will stain lungs to visualize airway disease severity and assess whether mechanical signaling pathways contribute to asthma development.