The Role of Protein Kinase C Alpha in the Skin and Cutaneous Wound Healing

Abstract

Chronic wounds represent a severe socio-economic burden and a key area of unmet clinical need. PKCalpha is ubiquitous in the skin, particularly the epidermis and functions in numerous pathways that are fundamental to wound repair. By utilising a global PKCalpha-/- mouse we have identified PKCalpha-regulated processes both in unwounded skin and during wound healing. PKCalpha-/- mice display considerably delayed wound healing with a dramatic reduction in re-epithelialisation. By analysing the ultrastructure of the epidermis, I have shown that this delay directly correlates with a failure of wound edge desmosomes to switch to a their adhesive properties. A major risk factor for the development of chronic wounds is age. Crucially, this delay in modulating cell adhesion is conserved in human chronic wounds and aged murine skin. Furthermore, manipulation of PKCalpha using an inducible bitransgenic mouse containing epidermal specific constitutively active PKCalpha can accelerate the modulation of desmosome adhesion and subsequently improve re-epithelialisation. Global gene expression analysis of PKCalpha-/- skin and wounds revealed further defects. Upon wounding, we observed a failure to correctly regulate expression of key collagen and Wnt signalling genes that are essential for correct and timely wound healing. Finally, intrinsic gene expression changes were identified in the skin of PKCalpha-/- mice, specifically a downregulation of multiple extracellular matrix genes. Of note was the downregulation of small leucine-rich proteoglycans which led to alterations to dermal collagen structure and skin tensile strength. These changes render the PKCalpha-/- skin susceptible to breaking and wound development. To conclude, we have identified multiple roles for PKCalpha intrinsically in the skin and also during cutaneous wound healing. Importantly, these intrinsic changes appear to predispose PKCalpha-/- skin to the development of cutaneous wounds and altered wound-specific processes that manifest in a delayed healing phenotype.

Date of Award	1 Aug 2014
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Matthew Hardman (Supervisor) & Mark Travis (Supervisor)