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Integrated in vitro model systems for investigating the role of connexins in coordination of cell migration proliferation and differentiation.

Reference	BB/C005058/1
Principal Investigator / Supervisor	Dr Patricia Martin
Co-Investigators / Co-Supervisors	Dr Malcolm Briden Hodgins
Institution	Glasgow Caledonian University
Department	Sch of Health and Life Sciences
Funding type	Research
Value (£)	66,447
Status	Completed
Type	Research Grant
Start date	01/09/2005
End date	30/11/2006
Duration	15 months

Abstract

The closure of an epidermal skin wound requires a series of complex events central to which is the coordination of cellular activities. The cells of the epidermis are connected together by a dynamic network of gap junction intercellular communication channels composed of different connexin protein subunits that are differentially expressed throughout the dermal layers. These channels permit the exchange of regulatory ions and molecules with different connexins having different physical properties. Recent evidence suggests that manipulation of Cx43 signalling events can alter wound healing rates and it is highly likely that the different connexins expressed in the epidermis are required to coordinate cell proliferation, migration and differentiation. We aim to adapt established methods for reconstructing epidermis in vitro to develop novel 3D model systems for analysing the roles of connexins in epidermal wound closure by using keratinocytes isolated from different connexin knockout and transgenic mice. To this end we have produced transgenic Cx26D66H and Cx26Del42E which provide models for mutant Cx26 channelopathies resulting in the inherited skin disorders Vohwinkels syndrome and palmoplantar keratoderma in man. We also have available Cx30, Cx31 and Cx43 knockout mice, thereby profiling the major connexins in the skin. These combinations of connexin knockouts will enable us to functionally dissect the role of individual connexins in the coordination of cellular behaviour in epidermal networks while maintaining the complexity of connexins profiled in the skin. Application of novel connexin mimetic peptides and RNAi technologies will extend the range of connexin knock-down combinations possible. New connexin mimetic peptides will also facilitate probing of acute responses to inhibiting specific connexins and will help to dissect gap-junctional from hemi- channel functions of connexins in integration of keratinocyte behaviour during wound closure. Such model systemswill allow us to address the role of individual connexins during epidermal stratification as well as their role during wound healing responses including cell migration, proliferation and differentiation. The advantages of such an integrated in vitro cell system over using intact animal model systems to allow us to study the mechanistics of intercellular communication as well as connexin behaviour in specific cell layers and how pharmacological modification of connexins at the RNA and protein level can alter would healing responses.

Summary

unavailable

Committee	Closed Committee - Biochemistry & Cell Biology (BCB)
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	X – not Funded via a specific Funding Scheme

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