The proposed research is part of program that seeks to determine why people with cystic fibrosis (CF) have chronic airway infections. The general hypothesis is that defective airway submucosal glands produce mucus that is under-hydrated, compromising mucus clearance and the bio-availability of antimicrobial and anti-inflammatory compounds. In previous work we showed a profound defect in the response of CF glands to agents that elevate cAMP. To progress from those observations we propose 4 specific aims.
Aim 1 : To determine how local (intrinsic) neurons, especially those containing VIP, control gland secretion directly and via interaction with cholinergic input.
Aim 2 : To study secretory mechanisms at the single cell level within four anatomical compartments of the glands: the serous acini, mucous tubules, collecting duct and ciliated duct. Cellular responses are quantified using differential interference contrast (DIC) time-lapse digital imaging with which we optically section isolated, functioning glands from control and CF subjects. We will study how each of the four compartments respond to agents that increase [cAMP]i, [Ca2+]i or both, in the presence of control solution (Krebs-bicarbonate buffer) or solutions in which ion substitutions or transport inhibitors are used to dissect the transport processes within the glands. We will also clarify mechanisms for fluid and protein secretion by serous and mucous cells: our imaging methods allow us to quantify individual exocytotic events.
Aim 3 : To determine the pH of luminal mucus within the 4 gland compartments by using ratiometric imaging of fluorescent indicators (BCECF) injected into the gland lumen.
Aim 4 : To patch clamp partially dissociated gland serous and mucous cells, to obtain evidence for against the hypothesis that CFTR in the only apical anion channel in serous cells and is absent from mucous cells. Successful completion of these aims will clarify the contribution of glands, which produce approximately 95% of airway mucus, to the mucus clearance and chemical shield components of airway innate defenses.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
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Mckeon, Catherine T
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Stanford University
Schools of Arts and Sciences
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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
Wu, Jin V; Krouse, Mauri E; Rustagi, Arjun et al. (2004) An inwardly rectifying potassium channel in apical membrane of Calu-3 cells. J Biol Chem 279:46558-65

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