(Taken directly from the application) The central hypothesis of our research is that the loss of CFTR-mediated, apical membrane chloride conductance is the fundamental physiological defect that leads to airways disease in cystic fibrosis. The general goal of our research is to confirm or negate that hypothesis. The most puzzling aspect of CF lung disease is how it begins. A direct attack on that question is not possible at present because no adequate animal model of human CF lung disease exists. Elsewhere, we propose a strategy to produce such a model. Here, we propose experiments that are feasible with available model tissues and that deal with two of most basic questions in CF research: how does CFTR operate as an ion channel, and what other chloride ion channels are important players in the lung. The proposal has 4 specific aims.
Aim 1 is to understand the mechanism and functional significance of natural """"""""lock-open"""""""" kinetics that we have discovered in CFTR channels of human airway cells.
Aim 2 is to test the hypothesis that some mutations in CFTR lead to disease in whole or in part because they interfere with CFTR's ability to display locked-open kinetics.
Aim 3 is to identify other chloride channels and determine their role in airway cell function.
Aim 4 is to study changes in channel populations that occur with epithelial cell polarization.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (SRC (06))
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Mckeon, Catherine T
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Stanford University
Schools of Arts and Sciences
United States
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Cho, Hyung-Ju; Joo, Nam Soo; Wine, Jeffrey J (2011) Defective fluid secretion from submucosal glands of nasal turbinates from CFTR-/- and CFTR (?F508/?F508) pigs. PLoS One 6:e24424
Wine, Jeffrey J; Joo, Nam Soo; Choi, Jae Young et al. (2011) Measurement of fluid secretion from intact airway submucosal glands. Methods Mol Biol 742:93-112
Cho, Hyung-Ju; Joo, Nam Soo; Wine, Jeffrey J (2010) Mucus secretion from individual submucosal glands of the ferret trachea. Am J Physiol Lung Cell Mol Physiol 299:L124-36
Choi, Jae Young; Khansaheb, Monal; Joo, Nam Soo et al. (2009) Substance P stimulates human airway submucosal gland secretion mainly via a CFTR-dependent process. J Clin Invest 119:1189-200
Ianowski, Juan P; Choi, Jae Young; Wine, Jeffrey J et al. (2008) Substance P stimulates CFTR-dependent fluid secretion by mouse tracheal submucosal glands. Pflugers Arch 457:529-37
Ianowski, Juan P; Choi, Jae Young; Wine, Jeffrey J et al. (2007) Mucus secretion by single tracheal submucosal glands from normal and cystic fibrosis transmembrane conductance regulator knockout mice. J Physiol 580:301-14
Wine, Jeffrey J (2007) Parasympathetic control of airway submucosal glands: central reflexes and the airway intrinsic nervous system. Auton Neurosci 133:35-54
Wine, Jeffrey J (2006) Acid in the airways. Focus on ""Hyperacidity of secreted fluid from submucosal glands in early cystic fibrosis"". Am J Physiol Cell Physiol 290:C669-71
Joo, Nam Soo; Irokawa, Toshiya; Robbins, Robert C et al. (2006) Hyposecretion, not hyperabsorption, is the basic defect of cystic fibrosis airway glands. J Biol Chem 281:7392-8
Wine, Jeffrey J; Joo, Nam Soo (2004) Submucosal glands and airway defense. Proc Am Thorac Soc 1:47-53

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