Cystic fibrosis (CF) is the most common severe autosomal recessive disease in Caucasian individuals. CF is characterized by an imbalance in the movement of salt and water across the airway surface, such that the overlying mucus layer becomes dehydrated, collapses onto the airway wall, and fails to be cleared from the airways. This impaired mucus clearance leads to chronic infection and airways obstruction, andultimately causes respiratory failure leading to premature death or lungtransplantation. Sodium absorption through the epithelial sodium channel (ENaC), which establishes an osmotic driving force for the absorption of airway surface liquid (ASL), is abnormally high in CF patients for unknown reasons. Furthermore, when the activityof ENaC is inhibited in CF, the ASL becomes hydrated and mucus clearance improves. Our preliminary work suggests that imbalances between proteases, which activate the channel, and endogenous protease inhibitors on the luminal airway surface causes sodium hyperabsorption in CF airways. The goal of this K08 application is to provide the PI with essential skills to develop into a successful academic physician and achieve independent scientific investigator status with a focus on airwayphysiology as it relates to CF. The PI will focus upon the regulation of airway surface liquid volume by ENaC in normal and CF airway epithelium. The primary scientific aims of this proposal are to (i) define the role of the protease/protease inhibitor balance in the physiological regulation of ENaC and ASL depth, (ii) determine which channel activating proteases and protease inhibitors are involved in the regulation of ENaC in the airway, and (iii)define the mechanism by which proteolytic processing of ENaC is altered in CF. To achieve his goal and complete these aims the PI will combine focused graduate course work with state-of-the-art laboratory methods to delineate the electrophysiology and biochemistry of ENaC in primary humanairway epithelial cells and relevant heterologous expression systems. Understanding the nature of proteolytic regulation of ENaC activityin normal and diseased airways will ultimately direct the development of novel therapies to mitigate sodium hyperabsorption and thereby restore normal ASL volume and mucus clearance in CF airways.
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| Butterworth, Michael B; Zhang, Liang; Heidrich, Elisa M et al. (2012) Activation of the epithelial sodium channel (ENaC) by the alkaline protease from Pseudomonas aeruginosa. J Biol Chem 287:32556-65 |
| Chen, Jingxin; Winarski, Katie L; Myerburg, Mike M et al. (2012) Probing the structural basis of Zn2+ regulation of the epithelial Na+ channel. J Biol Chem 287:35589-98 |
| Passero, Christopher J; Mueller, Gunhild M; Myerburg, Michael M et al. (2012) TMPRSS4-dependent activation of the epithelial sodium channel requires cleavage of the ?-subunit distal to the furin cleavage site. Am J Physiol Renal Physiol 302:F1-8 |
| Chen, Jingxin; Myerburg, Mike M; Passero, Christopher J et al. (2011) External Cu2+ inhibits human epithelial Na+ channels by binding at a subunit interface of extracellular domains. J Biol Chem 286:27436-46 |
| Rondanino, Christine; Poland, Paul A; Kinlough, Carol L et al. (2011) Galectin-7 modulates the length of the primary cilia and wound repair in polarized kidney epithelial cells. Am J Physiol Renal Physiol 301:F622-33 |
| Harvey, Peter R; Tarran, Robert; Garoff, Stephen et al. (2011) Measurement of the airway surface liquid volume with simple light refraction microscopy. Am J Respir Cell Mol Biol 45:592-9 |
| Myerburg, Michael M; Harvey, Peter R; Heidrich, Elisa M et al. (2010) Acute regulation of the epithelial sodium channel in airway epithelia by proteases and trafficking. Am J Respir Cell Mol Biol 43:712-9 |
| Corcoran, T E; Thomas, K M; Myerburg, M M et al. (2010) Absorptive clearance of DTPA as an aerosol-based biomarker in the cystic fibrosis airway. Eur Respir J 35:781-6 |
| Myerburg, Michael M; King Jr, J Darwin; Oyster, Nicholas M et al. (2010) AMPK agonists ameliorate sodium and fluid transport and inflammation in cystic fibrosis airway epithelial cells. Am J Respir Cell Mol Biol 42:676-84 |
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