Identification of extracellular matrix-derived biomarkers and targets in dystrophic epidermolysis bullosa

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Dystrophic epidermolysis bullosa (DEB) is a genetic skin blistering disorder caused by collagen VII deficiency. The most severe forms of the disease are also characterized by formation of slow healing wounds and progressive soft tissue fibrosis, which significantly contribute to disease morbidity. Furthermore, cutaneous squamous cell carcinoma driven by the injured and fibrotic dermal microenvironment is the major cause of death in severe DEB. Better treatment of the disease is urgently needed but development of causal therapies is hampered by concerns surrounding delivery, efficacy and safety. An alternative is to target the pathological manifestations occurring subsequent to skin fragility. Development of such manifestations is linked to specifc changes in the transcriptome, proteome and degradome, which can be employed as biomarkers of disease progression and severity. However, for both improved symptom-relief therapy and identification of robust biomarkers, an increased knowledge of the mechanisms involved in the establishment and progression of such manifestations is needed. By retrospective detailed analysis of the fibrotic dermal extracellular matrix (ECM), our approach will be to delineate the processes involved in its buildup with a focus on its major components, the fibrillar collagens and their partners. Establishment of a physiological dermal ECM occurs through regulated and coordinated activity of the epidermis and dermis, leading to collagen fibrillogenesis and ECM organization with biomechanical properties optimized to support skin function. In fibrosis, these processes are disrupted. In this proposal, we plan to comprehensively analyze the fibrotic ECM in order to characterize the most severely affected processes in DEB and to identify (i) novel biomarkers for improved monitoring of DEB disease stages during clinical trials and (ii) conceptually novel evidence-based therapeutic approaches to treat DEB.Our consortium brings together a German partner (Dept. Dermatology, University of Freiburg) and a French partner (LBTI-CNRS, University of Lyon) with internationally-renowned expertise in the fields of DEB disease and ECM biology. The project will be organized in 4 tasks with the following specific goals: 1) to characterize the dermal collagen matrix in DEB skin; 2) to analyze the influence of altered dermal-epidermal communication in DEB; 3) to evaluate the role of ECM remodeling proteinases in DEB fibrosis; 4) to validate, in patient samples, the clinical relevance of biomarkers identified in previous tasks.Together, these studies will provide essential information to understand the main factors contributing to DEB severity and will allow us to make significant progress towards the validation of both novel biomarkers and therapeutic targets. It is also expected that our proposal will have significant spin-off effects for the understanding and management of other types of inflammation- and fibrosis-driven pathological wounds.