Department of Medicine
University of Pittsburgh
Altered Proteolytic Processing of ENaC in the Pathogenesis of Cystic Fibrosis
TRAINEE
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| Michael Myerburg, M.D. |
MENTORS
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| Joseph Pilewski, M.D. | Thomas Kleyman, M.D. |
STUDY DESCRIPTION
Accumulating evidence indicates that muco-ciliary clearance is dependent on the presence of a thin layer of fluid, known as the airway surface liquid (ASL), which acts as a low viscosity medium that allows cilia to beat effectively. The ASL volume is normally maintained by the oppositely directed transport of Na+ and Cl- across the airway epithelium. It is believed that unregulated activity of epithelial sodium channels (ENaC) in cystic fibrosis (CF) causes excessive ASL absorption, leading to impaired ciliary function, mucus stasis, chronic infection, and premature respiratory failure. The cellular mechanisms that result in increased ENaC activity in CF airways are not known.
We hypothesize that proteolysis of ENaC subunits by proteases at the cell surface is a key mechanism for modulating sodium absorption. Furthermore, we hypothesize that endogenous protease inhibitors regulate the activity of channel activating proteases, and that aberrant proteolytic regulation of ENaC in CF contributes to disease pathogenesis.
Accordingly, the specific aims are to:
- Define the role of the protease/protease inhibitor balance in the physiological regulation of ENaC and ASL volume.
- Determine which channel activating proteases and protease inhibitors establish and maintain a constitutively active pool and a regulated pool of ENaC in airway epithelium.
- Define the mechanism by which proteolytic processing of ENaC is altered in CF.
This project has led to 3 first-authored publications, an NIH funded K08, and a Cystic Fibrosis Foundation grant for Dr. Myerburg.
ENaC is regulated by the relative balance between membrane tethered proteases, which activate the channel, and soluble protease inhibitors that are present in the airway surface liquid. As shown in the schematic below, this “protease – protease inhibitor balance” establishes an auto-regulatory mechanism to maintain optimal airway surface liquid (ASL) hydration.