Glass, BJL; (2014) The role of connexins in tissue injury repair. Doctoral thesis , UCL (University College London).

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Abstract

Skin integrity is essential for sustaining life and it is important to understand the processes involved in its maintenance and repair. There are several key stages involved in wound healing that rely on the complex communication through gap junctions and their connexins to ensure the resolution of the wound. Gap junctions are expressed in all cells linked with tissue repair and provide a regulated pathway linking the cytoplasm of neighbouring cells and allowing signals to pass freely between the two. In the skin there are three key connexins (Connexins 26, 30 and 43) that undergo dynamic changes and regulate the stages of wound closure. To date, extensive research has shown that inhibiting Cx43 expression can achieve significant improvements in wound repair. Synthetic connexin mimetic peptide Gap27 which possess a conserved homology to the second extracellular loop of Cx43 is now being considered as a candidate to improve the rate of wound repair. At low concentrations Gap27 has been shown to block hemichannels but can target gap junctional intercellular communication at higher concentrations and for longer incubation periods. By using Gap27 as a tool, this thesis explores the importance of connexins, hemichannels and gap junctions in tissue injury and repair. I have dissected out the relative contributions of connexins and their involvement with hemichannels and gap junctions in wound repair while investigating if and how Gap27 reduces other connexins. Further work using in vitro wound healing models has shown how Gap27 can enhance the rate of wound healing in early stages. In the second half of this thesis I continue to use Gap27 to investigate the connexin based communication involved in the spread of cell death and damage during ischemia reperfusion injury in vitro and in vivo. The potential therapeutic implications of the wound healing properties of Gap27 are exciting, novel and promising.

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