The obstructive pulmonary diseases (OPD), cystic fibrosis, chronic bronchitis, bronchiectasis, emphysema, and asthma, are inflammatory diseases with very different inflammatory cell profiles, cytokine responses, etc; mucin hypersecretion from airway surface goblet cells and submucosal mucous cells represents a singular, shared characteristic. Conceptually, mucin hypersecretion may result from inflammation-driven goblet cell meta/hyperplasia and/or elevated rates of mucin secretion. Although the best long-term treatment for OPDs will likely target the individual causes of inflammation, it is notable that acute relief to OPD patients, generally, could be achieved by selectively inhibiting mucin secretion. Possibly more important, such an inhibitor would help to open mucus-clogged airways to enable efficient, inhalation-based treatment of the underlying disease. Hence, our long-range goal is to study the molecular mechanisms by which mucin granule exocytosis in airway goblet cells is regulated, to identify molecular targets for selective drug therapies. It is well known that goblet cell mucin secretion is regulated by extracellular ATP and UTP acting through the P2Y2 receptor (P2Y2-R), and that the subsequent secretory response is mediated by the phospholipase C pathway through PKC and Ca2+. Yet, our knowledge of the signaling pathways involved in goblet cell regulation is incomplete. For instance, the effects of muscarinic agonists are highly controversial, there are no data relevant to the mechanisms and pathways underlying the regulation of basal mucin secretion from airway goblet cells, and the effects of agents signaling through receptors acting via tyrosine kinase pathways are uknown, though many of them do have metaplastic effects on the airways epithelium. At the molecular level, we know very little of the effectors regulating exocytosis beyond the identities of the intracellular messengers. Hence, we propose a broadly based approach using the primary cultures of human bronchial epithelial cells, airways epithelium from human lungs and genetically manipulated mice rendered metaplastic for goblet cells, and SPOC1 goblet cells to further delineate the intracellular molecular regulation of mucin granule exocytosis from airway goblet cells, and to extend our knowledge of the signaling pathways regulating goblet cell function into new areas involving basal mucin secretion, type I receptor and involvement, and mechanical shear effects.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063756-06
Application #
6875039
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Banks-Schlegel, Susan P
Project Start
2000-02-15
Project End
2008-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
6
Fiscal Year
2005
Total Cost
$291,277
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Physiology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Abdullah, Lubna H; Wolber, C├ędric; Kesimer, Mehmet et al. (2012) Studying mucin secretion from human bronchial epithelial cell primary cultures. Methods Mol Biol 842:259-77
Kreda, Silvia M; Davis, C William; Rose, Mary Callaghan (2012) CFTR, mucins, and mucus obstruction in cystic fibrosis. Cold Spring Harb Perspect Med 2:a009589
Schmid, Andreas; Clunes, Lucy A; Salathe, Mathias et al. (2011) Nucleotide-mediated airway clearance. Subcell Biochem 55:95-138
Tuvim, Michael J; Mospan, Andrea Rossi; Burns, Kimberlie A et al. (2009) Synaptotagmin 2 couples mucin granule exocytosis to Ca2+ signaling from endoplasmic reticulum. J Biol Chem 284:9781-7
Zhu, Yunxiang; Ehre, Camille; Abdullah, Lubna H et al. (2008) Munc13-2-/- baseline secretion defect reveals source of oligomeric mucins in mouse airways. J Physiol 586:1977-92
Davis, C William; Dickey, Burton F (2008) Regulated airway goblet cell mucin secretion. Annu Rev Physiol 70:487-512
Davis, C William; Lazarowski, Eduardo (2008) Coupling of airway ciliary activity and mucin secretion to mechanical stresses by purinergic signaling. Respir Physiol Neurobiol 163:208-13
Rossi, Andrea H; Salmon, Wendy C; Chua, Michael et al. (2007) Calcium signaling in human airway goblet cells following purinergic activation. Am J Physiol Lung Cell Mol Physiol 292:L92-8
Ehre, Camille; Zhu, Yunxiang; Abdullah, Lubna H et al. (2007) nPKCepsilon, a P2Y2-R downstream effector in regulated mucin secretion from airway goblet cells. Am J Physiol Cell Physiol 293:C1445-54
Abdullah, Lubna H; Davis, C William (2007) Regulation of airway goblet cell mucin secretion by tyrosine phosphorylation signaling pathways. Am J Physiol Lung Cell Mol Physiol 293:L591-9

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