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Abstract
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| Grant Number: |
5R01HL063302-02 |
| PI Name: |
BALLARD, STEPHEN T. |
| PI Email: |
sballard@usamail.usouthal.edu |
| PI Title: |
ASSOCIATE PROFESSOR |
| Project Title: |
AIRWAY SUBMUCOSAL GLANDS AND |
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CYSTIC FIBROSIS DISEASE |
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| Abstract: DESCRIPTION(adapted from applicant's abstract): Mortality in cystic fibrosis (CF) typically results from the pulmonary complications of the disease, which include progressive obstruction of the airways with a thick dehydrated mucus, reduced mucociliary transport, chronic airway infections, and bronchiectasis. While CF is known to be caused by mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator protein (CFTR), a cAMP-regulated anion channel, the functional link between defects in this channel function and the pulmonary pathogenesis of CF is unclear and controversial. Using porcine airways, the principal investigator has recently shown that CFTR normally mediates secretion of both Cl- and HCO3 by submucosal glands of the airways and that this process drives secretion of gland liquid. When gland liquid secretion is blocked by applying selective C1- and HCO3 secretion inhibitors, airways undergo changes that parallel those observed in early CF airway disease-- mucus obstruction of gland ducts, production of an abnormally thick dehydrated mucus, and reductions in mucociliary transport. From these observations, the principal investigator hypothesizes that CF lung pathology is the inevitable consequence of impaired Cl- and HCO3 secretion from submucosal glands. In support of this hypothesis, the applicant proposes the following aims. First, the mechanism by which gland liquid secretion inhibitors reduce mucociliary transport will be determined. Second, the role of secretory vesicles in mucus gel formation will be studied to better understand the mechanism and dynamics of mucus maturation in airways. Third, the efficacy and mechanism of potential airway secretogogues will be evaluated to identify possible CFTR-independent routes which could be manipulated for therapeutic induction of liquid secretion. Fourth, the ability of inhibitors of Cl- and HCO3 secretion to reproduce mucus obstruction of airways will be determined in isolated, perfused lung lobes. These proposed studies will provide critical information for understanding the role of glandular Cl- and HCO3 secretion in the etiology of CF. If this hypothesis is confirmed, these studies could form the important basis of therapeutic strategies for the treatment of this lethal disease. |
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Thesaurus Terms:
chloride channel, cystic fibrosis, mucus, pathologic process, respiratory airway clearance, respiratory epithelium, secretion
bicarbonate, inhibitor /antagonist
perfusion, swine
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| Institution: |
UNIVERSITY OF SOUTH ALABAMA |
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307 N UNIVERSITY BLVD |
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MOBILE, AL 36688 |
| Fiscal Year: |
2002 |
| Department: |
PHYSIOLOGY |
| Project Start: |
10-JUN-2001 |
| Project End: |
30-APR-2005 |
| ICD: |
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE |
| IRG: |
MEDB |
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