We have previously shown that the height (volume) of normal (NL) airway surface liquid (ASL) is regulated, but the underlying mechanisms are unknown and the relevance to disease (e.g., cystic fibrosis; CF) controversial. Our long-term goal is to understand how ASL volume is autoregulated in NL and CF airway epithelia under physiological conditions. The specific hypothesis behind the proposed research is that ATP and ADO act as shear stress-dependent signals encoded in the ASL to autoregulate NL and CF ASL volume by modulating ion transport (Na+absorption and CI-secretion). This hypothesis is based on data obtained with a novel system that mimics the shear stress imparted by the lung in vivo during normal tidal breathing. Shear stress induced a realignment of the actin cytoskeleton in the direction of the applied shear, increased ATP release into the airway surface liquid and increased the distance between the 5' ectonucleotidase (the ecto-enzyme responsible for making adenosine on airway surfaces) and the A2b adenosine receptor, as measured by fluorescence resonance energy transfer (FRET). These studies provide a first step towards understanding how shear stress may be sensed and transduced in airway epithelia. We also found that principal effectors were activated by shear stress: extracellular purine nucleotide (ATP)- and nucleoside (adenosine)-dependent pathways for ASL autoregulation were increased in normal airway epithelia while cystic fibrosis airways relied solely on a motion-dependent ATP pathway to rebalance abnormal CF ion transport and adjust ASL height to levels adequate for mucus transport. Based on these observations, the specific aims of this proposal are (1) to identify sensors of ASL volume, (2) to understand how ASL volume regulation is transduced and (3) to normalize CF airway surface liquid volume regulation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL074158-03
Application #
7177545
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Banks-Schlegel, Susan P
Project Start
2005-04-01
Project End
2008-02-28
Budget Start
2007-03-01
Budget End
2008-02-28
Support Year
3
Fiscal Year
2007
Total Cost
$207,651
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Esther Jr, Charles R; Sesma, Juliana I; Dohlman, Henrik G et al. (2008) Similarities between UDP-glucose and adenine nucleotide release in yeast: involvement of the secretory pathway. Biochemistry 47:9269-78
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Coakley, Ray D; Sun, Hengrui; Clunes, Lucy A et al. (2008) 17beta-Estradiol inhibits Ca2+-dependent homeostasis of airway surface liquid volume in human cystic fibrosis airway epithelia. J Clin Invest 118:4025-35
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Thelin, William R; Kesimer, Mehmet; Tarran, Robert et al. (2005) The cystic fibrosis transmembrane conductance regulator is regulated by a direct interaction with the protein phosphatase 2A. J Biol Chem 280:41512-20

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