Modeling of wound repair and inflammation in the Drosophila embryo

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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 one way to do this is by turning to a very simple model, the fruitfly, Drosophila. Using the fly it is possible to make movies of healing wounds in living animals and observe precisely how individual cells are involved at every stage. Moreover, Drosophila also have hugely simpler genetics so we can relatively easily determine which genes are pivotal in each component of each stage of the repair process. We have already shown that for the wound closure step and for the associated inflammatory step where white blood cells are recruited to the wound, much of what we find in flies holds true for mice and man. Here we propose using Drosophila to gain a fast track understanding of:1. How molecular switches in skin cells (both those at the wound edge and the ones further back), respond to the wound signals to assemble the actomyosin contractile cables (just like in muscle) that move the cells forward to heal the wound. These signals will not only be chemical but we think also mechanical, like stretch, and our studies in fly will let us investigate this too. We also want to know which of the genes that are switched on in the wound edge cells are most important, and what the steps are that enable them to be switched on. This fundamental knowledge will lend clues when designing potential therapeutics to "kick start" healing in patients suffering from chronic, non-healing wounds.2. What signals draw white blood cells to the wound and how do they sense these signals? Since the white blood cells are there to deal with wound infection we want to watch how they do this and also to determine what it is that forces them to leave the wound site when healing is complete because many human pathologies are a consequence of inflammation failing to resolve. Being able to artificially modulate the inflammatory response in patients would enable us to prevent some of the negative consequences of inflammation at wound sites including fibrosis. The fly offers a chance to take the first steps in achieving this goal.Because we are doing all these experiments in flies which have a very short lifecycle and very powerful genetics, we can find answers to these questions much faster than would be possible in any other model organism, but it will be important to take what we discover in flies and apply it to more clinically relevant models. This important step is made considerably easier for us since one of our labs also works on vertebrate wound healing models in zebrafish and mouse and has clinical collaborations too with a group in Cardiff that have a wound healing clinic dealing with human patient samples.