Investigating the functions and therapeutic potential for Eph receptors and ephrins during wound repair and inflammation

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Wound healing is the body?s process of repairing damaged tissue and takes place for all wounds, be they a nick to the finger or the repair of internal organs after abdominal surgery. There are many occasions when tissue repair fails, leading to chronic non-healing wounds such as venous leg ulcers which are a huge clinical burden for elderly patients and suffered by about 500,000 people in the UK. Equally, the process can be too exuberant leading to fibrosis and scarring as a consequence of excessive contraction, healing and inflammation. In order to understand how tissue repair goes awry and how it might be improved, we need to better understand the process, and essentially that means figuring out how the dormant tissues of unwounded skin (or other organs), are awakened upon damage, allowing them to migrate and fill the gap created by the wound, and how they know when to stop when the wound is healed.The studies outlined here are to investigate a family of receptors and the proteins that bind to them, the Ephs and ephrins, that, despite being very well studied in embryonic development and in cancer and implicated in regulating the ?starting and stopping? of cell migrations in both these scenarios, have not previously been studied in the wound repair process. We have preliminary data in mouse that shows how several members of this large family of receptors become expressed and activated in particular cell types during the wound closure process, in ways that are suggestive of their being key players, and we will look to see whether the same is true in human wound tissues and whether biopsies from pathological wounds, in particular longstanding leg ulcers, have an altered pattern of these receptors. We will then test whether modulating particular Eph family members will allow us to alter and improve some aspects of healing while not affecting others, with a view to designing therapies that can either ?kickstart? the tissues of a non-healing wound to repair itself or shut down the repair machinery in a wound that is too inflamed and/or too exuberant and likely to form a bad scar.