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.
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