In order for gas exchange to occur in an optimum fashion, the alveolar space must remain free of fluid. Convincing evidence indicates that active Na+ transport across the alveolar epithelium in vivo contributes to the reabsorption of the fetal fluid and to the maintenance of fluid free alveolar spaces in adult lungs, especially when either alveolar permeability to plasma proteins or lung hydrostatic pressures are increased. Na+ ion reabsorption occurs through the amiloride sensitive epithelial Na+ channels (((( ENaC) and poorly characterized cation channels. Based on the exciting preliminary data presented in this application, we hypothesize that a newly described protein (( ENaC) fundamentally alters the biophysical properties of ((( ENaC-type channels and renders them sensitive to regulation via the cGMP/PKG axis. The main goals of this application are: 1) to fully characterize the biophysical and pharmacological properties of ( ENaC type channels in both Xenopus oocytes and human lung epithelial cells;2) to investigate the regulation of ( ENaC-containing channels by cGMP in oocytes and human alveolar cells;and 3) to assess the contribution of ( ENaC to vectorial Na+ transport across human epithelial cell monolayers mounted in Ussing chambers and mouse lungs in vivo using state-of-the-art biochemical, molecular biological, electrophysiological and physiological techniques. The following specific hypotheses will be tested: 1) ( ENaC-containing homo- and heteromeric channels expressed in Xenopus oocytes have diverse biophysical properties;2) cGMP regulates (ENaC-containing homo- and heteromeric channels but not ((( channels expressed in Xenopus oocytes;and 3) ( ENaC contributes to the non-((( ENaC Na+ currents across primary human alveolar type II (ATII) and H441 monolayers and to alveolar fluid clearance in mouse lungs. The subject matter of this research is timely and important. Results of these studies may form the molecular basis for development of new therapeutic strategies (such as cGMP delivery) to combat pulmonary edema.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL087017-04
Application #
7577411
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Harabin, Andrea L
Project Start
2007-02-01
Project End
2012-01-31
Budget Start
2009-02-01
Budget End
2010-01-31
Support Year
4
Fiscal Year
2009
Total Cost
$275,000
Indirect Cost
Name
University of Texas Health Center at Tyler
Department
Type
Organized Research Units
DUNS #
800772337
City
Tyler
State
TX
Country
United States
Zip Code
75708
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