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Research GroupsPathogenesis and treatment of cystic fibrosis

Research Focus 2: Ion transport defect in cystic fibrosis airways

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Increased airway Na+ absorption mediated by epithelial Na+ channels (ENaC) and deficient CFTR-mediated Cl- secretion are basic defects that play a critical role in the pathogenesis of CF lung disease. ENaC is a transmembrane protein composed of three individual subunits (α, β, γ) and constitutes the rate limiting pathway for absorption of salt and water from airway surfaces, whereas fluid secretion is mediated by CFTR and alternative Ca2+-activated Cl. channels (CaCC). In CF airways and mice overexpressing ENaC in airway epithelia (Mall. M. et al, Nat. Med., 2004), increased ENaC activity leads to airway surface liquid (ASL) depletion, which impairs mucociliary clearance constituting an important innate defense mechanism of the lung.

In this project, we use CF mouse models to study the mechanisms underlying the dysregulation of ion transport and ASL homeostasis in native airway tissues. Further, we test small molecule compounds that target epithelial signalling including membrane-permeant derivatives of myo-inositol 3,4,5,6-tetrakisphosphate (Moody, M. et al, Am. J. Physiol. Cell Physiol., 2005) for their efficacy in counteracting the basic ion transport defects and improving hydration and host defense mechanisms on CF airway surfaces. Successful approaches in native airway tissues will be further evaluated for their therapeutic benefits in mouse models of CF lung disease.

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