Role of astacin-like proteinases in physiological wound healing and scarring

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Defective wound healing in skin, leading to chronic wounds or fibroproliferative disorders such as hypertrophic scarring, is a major healthcare challenge worldwide for which the market is estimated to be at least 10 billion euros and is destined to increase with the ageing population. The current lack of pathogenesis-specific therapies is largely due to the complexity of the multiple stages involved in wound healing and to the lack of information about the connectivity between the different players involved. This project aims to identify the roles of an emerging family of metalloproteinases, called astacin-like proteinases (ALPs), in normal and pathological wound healing.Unlike the matrix metalloproteinases, known largely for their roles in tissue degradation, the astacin-like proteinases, among which the bone morphogenetic protein-1/tolloid-like proteinases (BTPs) and meprin alpha and meprin beta are those found in skin, have recently been shown to orchestrate several aspects of tissue repair. Particularly important in this context are cytokine and growth factor activation, angiogenesis and extracellular matrix (ECM) assembly. Recent advances in quantitative proteomics to study proteolysis in complex samples and in the development of inhibitors directed against ALPs have made it possible to take an integrative approach to understanding the roles of these proteinases, which appear to have both overlapping and complementary substrate specificities, in tissue remodeling. The project will be multidisciplinary, including i) the characterization and application of new phosphinic peptide-type inhibitors specifically targeting individual ALPs, ii) the use of mouse models, human biopsies and skin primary cells to characterize the expression patterns of different ALPs in skin during the course of normal and fibroproliferative wound healing, iii) the application of quantitative proteomics (TAILS method) for the identification of ALP substrates, iv) the validation of these substrates in vitro and in vivo, and v) the use of the data (expression profiles, substrates) and tools (inhibitors) made available in the project to propose and test novel therapeutic strategies for scarring targeting either individual ALP members or subfamilies, using the above mouse models. The partners from Kiel and Freiburg have complementary expertise in ALPs, protease activity assays, quantitative proteomics, mouse models, fibrosis, and wound healing. The knowledge acquired during the course of the proposed project will form the basis for the development of new therapeutic strategies for the prevention and treatment of wound healing disorders.