Embryos heal wounds very rapidly and efficiently and without leaving a scar. They appear to do this using a very similar portfolio of cellular tools to those used by embyos to undergo the natural morphogenetic movements of development. We hope that studying these parallels will help us better understand embryonic tissue movements and also suggest ways in which we might make adult tissues repair more efficiently. Using live confocal imaging of transgenic Drosophila embryos expressing gfp-actin in epithelial tissues we have compared repair of laser-generated epithelial wounds with the paradigm morphogenetic process of dorsal closure and show that remarkably similar actin-based actin machineries (an actomyosin pursestring and dynamic filopodia and lamellipodia) drive these two processes. It seems that very similar mechanisms may also be used by vertebrate embryos to zipper epithelial seams together, for example as the eyelids fuse during foetal development. We are currently interested in imaging the signalling episodes that direct the "starting" and "stopping" of these epithelial fusion and wound closure processes.
In adult mammalian skin wounds we see several hundred genes upregulated, many of these in the leading edge epidermal cells, and our recent studies indicate that a subset of these genes may first be epigenetically "unsilenced" by transient downregulation of the polycomb complex proteins and coincident upregulation of histone demethylases.
We have also become interested in the inflammatory response that is an inevitable consequence of any repair process in adult tissues. Our experiments in embryonic mice (where there is no inflammatory response), and in the neonatal PU.1 null mouse, which is genetically lacking the key leukocyte lineages, suggest that an inflammatory response is not essential for repair and may indeed be causal of fibrosis in post-embryonic animals. Consequently, we have used a microarray approach with this mouse in order to identify a portfolio of candidate inflammation/fibrosis genes and have begun to knock down each of these genes in turn to discover whether this might improve repair. When we knock down one of these inflammation-dependent genes, osteopontin, we find significantly improved healing without a scar. We have also established models of inflammation in the Drosophila embryo and in the translucent zebrafish larval tail fin, which allow us to make DIC movies of the inflammatory response and to dissect the genetics of inflammation, including the precise roles for each of the small GTPases and their effectors, in particular WASp, in recruitment of inflammatory cells to the wound site.
Most recently, we have used the translucent zebrafish larvae to compare the innate immune response to a wound and to "transformed" cells as they proliferate to form tumours in the skin. Our studies have shown that the same signal, H 2O 2, is the attractant in both situations and that immune cells impart some trophic signal(s) that encourage growth of transformed cells.
Paul Martin did his undergrad degree at Sussex and then a PhD with Julian Lewis at King’s London, before setting up lab in Oxford Anatomy; he moved to UCL Anatomy where he was for 10 years and then in 2003 moved to a joint position in Bristol’s Biochemistry and Physiology Departments. His lab works on wound healing and has established models to study repair and inflammation in mouse and zebrafish and Drosophila. The current twin foci of his lab are to investigate the genetics and cell biology of wound inflammation, in order to learn how best to modulate the inflammatory response to prevent fibrosis, and identifying parallels between wound and cancer-triggered inflammation. He was elected a Fellow of the Academy of Medical Sciences in 2011 and to membership of EMBO in 2012.
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