About the Project
Lung damage is associated with impaired clearance mechanisms due to disease-specific triggers of airways dehydration. In normal airways, the epithelial sodium channel (ENaC) is predominantly silent however a protease-antiprotease imbalance present in chronic lung disease can cause a dysregulation of ENaC leading to increased Na+ absorption, airways dehydration, thickened mucus and impaired mucociliary clearance (MCC). As restoration of normal airway clearance mechanisms would serve to reduce the risk/number of life-limiting cycles of infection and lung injury, inhibition of ENaC represents an attractive therapeutic strategy for repiratory medicine, independent of etiology of disease.
We have already shown, using primary human CF bronchial epithelial cells, that first-in-class, highly selective, sub-nanomolar inhibitors, some of which are currently being developed as drug candidates, are highly effective inhibitors of ENaC signaling leading to an increase in airway surface liquid. The objective of this study is to see if similar beneficial effects can be observed using primary human airway epithelial cells derived from COPD donors. This project will conduct further mechanistic studies on ENaC and airways hydration, but also aims to explore other potential therapeutic benefits to include impact on inflammation and airway remodeling (fibrogenesis) as well as suppression of signaling pathways which could potentially reduce the muco-secretory/obstructive phenotype associated with COPD. Importantly, these studies directly align to the strategic research interests of the Martin group, and a collaborative relationship with an industry partner and provide opportunity for the successful applicant to benefit from the significant expertise of the research group.
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