Airway epithelial cells are vital to normal lung function. By forming and maintaining a cellular barrier and being responsible for mucociliary clearance and transepithelial ion transport, epithelial cells protect he airways from infection, dehydration and accumulation of inhaled material. A failure of one or more of these mechanisms commonly contributes to chronic obstructive lung disease. All of these epithelial functions utilize Ca2+ as a regulatory signal and require cooperative cell activity. However, the mechanisms of Ca2+ signaling and intercellular communication and the consequences that Ca2+ signals have for epithelial physiology is poorly understood. We have discovered that two types of Ca2+ signaling occur in epithelial cells non-propagating Ca2+ oscillations and propagating intercellular Ca2+ waves. We hypothesize that Ca2+ oscillations regulate individual cell function whereas propagating Ca2+ waves coordinate multicellular activity and that the principles underlying these Ca2+ signals are different. We intend to test these hypotheses by characterizing the mechanisms of Ca2+ signaling in airway epithelial cells and by determining the consequences that Ca2+ signaling has for ciliary activity and the control of mucociliary clearance, ion channel activity and the regulation of the periciliary layer, and wound healing to maintain the cellular barrier of the airways. Specifically, we will (1) determine, with digital video microscopy and Ca2+ specific dyes, if intercellular Ca2+ waves via gap junctions by a Ca2+ independent regeneration of inositol triphosphate, (2) characterized the properties of epithelial intracellular Ca2+ oscillations to determine why Ca2+ oscillations do not propagate to adjacent cells, (3)determine if intercellular Ca2+ signaling initiates and orients the early healing responses of airways epithelium to trauma induced by physical or chemical agents, (4) determine the consequences that Ca2+ oscillations and intercellular C2+ waves have for ion channel activity associated with periciliary fluid regulation and (5) determine how Ca2+ signaling regulates ciliary activity and mucociliary transport by epithelia cells. By understanding the role of Ca2+ signaling in these research will not only contribute to our knowledge of the pathophysiology of airway epithelial cells, but will also significantly contribute to our understanding of the principles of signal transduction and intercellular communication in non-excitable cells.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL049288-04
Application #
2378784
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1993-12-01
Project End
1999-02-28
Budget Start
1997-03-01
Budget End
1998-02-28
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Physiology
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655
Zhang, Luo; Han, Demin; Sanderson, Michael J (2005) Effect of isoproterenol on the regulation of rabbit airway ciliary beat frequency measured with high-speed digital and fluorescence microscopy. Ann Otol Rhinol Laryngol 114:399-403
Bergner, Albrecht; Sanderson, Michael J (2003) Airway contractility and smooth muscle Ca(2+) signaling in lung slices from different mouse strains. J Appl Physiol 95:1325-32; discussion 1314
Zhang, Luo; Sanderson, Michael J (2003) Oscillations in ciliary beat frequency and intracellular calcium concentration in rabbit tracheal epithelial cells induced by ATP. J Physiol 546:733-49
Zhang, Luo; Sanderson, Michael J (2003) The role of cGMP in the regulation of rabbit airway ciliary beat frequency. J Physiol 551:765-76
Bergner, Albrecht; Sanderson, Michael J (2002) ATP stimulates Ca2+ oscillations and contraction in airway smooth muscle cells of mouse lung slices. Am J Physiol Lung Cell Mol Physiol 283:L1271-9
Bergner, Albrecht; Sanderson, Michael J (2002) Acetylcholine-induced calcium signaling and contraction of airway smooth muscle cells in lung slices. J Gen Physiol 119:187-98
Leybaert, L; Sanderson, M J (2001) Intercellular calcium signaling and flash photolysis of caged compounds. A sensitive method to evaluate gap junctional coupling. Methods Mol Biol 154:407-30
Fry, T; Evans, J H; Sanderson, M J (2001) Propagation of intercellular calcium waves in C6 glioma cells transfected with connexins 43 or 32. Microsc Res Tech 52:289-300
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Paemeleire, K; Martin, P E; Coleman, S L et al. (2000) Intercellular calcium waves in HeLa cells expressing GFP-labeled connexin 43, 32, or 26. Mol Biol Cell 11:1815-27

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