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Interactions between cyclic AMP and calcium signalling pathways in airway smooth muscle cells.

Reference	BB/I015574/1
Principal Investigator / Supervisor	Professor Colin Taylor
Co-Investigators / Co-Supervisors	Dr Mark Dowling
Institution	University of Cambridge
Department	Pharmacology
Funding type	Skills
Value (£)	91,932
Status	Completed
Type	Training Grants
Start date	01/10/2011
End date	30/09/2015
Duration	48 months

Abstract

unavailable

Summary

Ca2+ and cAMP are delivered to cells as spatially organised signals and reciprocal interactions between them are widespread. In bronchial airways, for example, Ca2+ is the primary control of contraction, via activation of myosin light chain kinase, while receptors that evoke cAMP formation cause relaxation. Both pathways are targets of drugs used to treat asthma and chronic obstructive pulmonary disease (COPD), with agonists of beta2-receptors and antagonists of M3 muscarinic receptors in widespread clinical use. In combination therapy, these drugs act at least additively and perhaps synergistically,but the nature of the interactions is undefined. In human bronchial airway smooth muscle cells (BASMC), cAMP attenuates Ca2+ signals and the Ca2+-sensitivity of the contractile apparatus; and Ca2+ attenuates cAMP signalling. The mechanisms underlying these physiologically and clinically important interactions are unresolved. Hitherto interactions between M3 and beta2 receptors have relied on heterologous expression in cell lines, but they need to be explored in native human tissues that retain an appropriate cohort of signalling proteins. Novartis is developing combination therapies for COPD, but there is presently no human pre-clinical model for assessment of their efficacy, and limited knowledge from which to identify possible drug targets downstream of receptors. Human bronchial airway smooth muscle cells (BASMC) in culture largely retain their native phenotype for up to 10 passages, but transfection is required to maintain normal levels of M3 receptors. These cells currently provide the best model for signalling analyses in BASMC. Our aims are to identify sites of interaction between cAMP and Ca2+ in human BASMC stimulated with agonists of beta2 and M3 receptors.

Committee	Not funded via Committee
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	Training Grant - Industrial Case

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