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Tissue remodelling results from the concerted action of numerous extracellular and cell surface proteases. These act to synchronize the synthesis and degradation of the extracellular matrix with the control of cytokine activity and cell signalling in order to create appropriate environments for cell proliferation, migration and differentiation. Wound healing is a complex example of tissue remodelling that includes several steps occurring either concomitantly or successively during the process of repair : haemostasis, inflammation, angiogenesis, re-epithelialisation, granulation tissue formation, wound contraction and matrix remodelling. The main extracellular and cell surface proteases involved in wound healing are serine proteases and metalloproteases of the metzincin family. Our group focusses on a subfamily of metzincin proteases, the BMP-1/tolloid-like proteases which are known to be essential for extracellular matrix assembly and growth factor activation but whose functions in wound healing have not yet been clearly described.

Our main goals are to identify novel substrates of BMP-1/tolloid-like proteases, to describe their proteolytic activity at the cellular and tissue level and to understand their complex regulation by endogenous activators and inhibitors (for example Procollagen C-Proteinase Enhancers : Fig. 1).

We use an integrative approach, combining biochemical and structural approaches (e.g. protein production and purification, crystallography, SAXS, SPR, enzyme kinetics) with cellular studies (cultures of primary cells and cell lines, high-throughput quantitative proteomics) and in vivo models of wound healing and scarring (Fig. 2). As defective tissue repair following injury and infection is a major health concern (affecting most organs including skin and cornea but also heart, lung, liver and kidney), our research, while fundamental in nature, has important biomedical implications.

Figure 2 : Electron micrographs showing stromal disorganization 14 days after injury in mouse cornea (courtesy of F. Malecaze and S. Galiacy) (courtesy of F. Malecaze and S. Galiacy)

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