Dystrophic epidermolysis bullosa: quantitative proteomics approach to molecular mechanisms

• Applicants: Professor Dr. Jörn Dengjel; Dr. Alexander Nyström
• Subject Area: Dermatology ; Biochemistry
• Term: from 2012 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 219062131

Dystrophic epidermolysis bullosa (DEB) is a monogenic skin disorder characterized by loss or perturbation of collagen VII functions. Patients exhibit diminished epidermal-dermal adhesion, skin blistering and subsequent scarring. Up to now, more than 800 different mutations have been disclosed in the gene COL7A1 which encodes collagen VII. A broad range of clinical phenotypes is observed, which is partially due to the nature of respective mutations and which range from isolated nail dystrophy, through localized blistering in the extremities, to generalized blistering and mutilating deformities, mucosal involvement, increased risk of skin squamous cell carcinoma and failure to thrive with premature demise. In the most severe form of the disease, due to null mutations, both collagen VII protein and anchoring fibrils are absent. In milder forms, based on missense mutations, such as glycine substitutions within the triple helical domain, collagen VII is present, but has altered stability and leads to altered functionality of anchoring fibrils. Although genotype-phenotype correlations in DEB have a certain dose-dependence, with individuals expressing partially functional collagen VII being more mildly affected than individuals completely devoid of collagen VII, it has become evident that this does not strictly apply for many individuals. This observation clearly indicates that disease manifestation in DEB is not only governed by loss of collagen VII function but importantly is also determined by secondary mechanisms. We aim to generate new knowledge of underlying molecular mechanisms of DEB by identifying hitherto unknown genes and proteins involved in disease pathogenesis and phenotypic variability. We study skin fibroblast-keratinocyte crosstalk, perturbed signal transduction and the role of inflammation in disease progression using cell culture as well as mouse models. Combination of a mouse model, cell biological and protein biochemical approaches, together with mass spectrometry-based proteomics and immunohistochemistry and -fluorescence will generate comprehensive datasets that will allow a better understanding of clinical phenotypes in DEB. Clinical phenotypes will be linked to molecular pathways, thus establishing an important prerequisite for the design of novel molecular therapies. We aim at a systems-level understanding of protein dynamics in DEB and envision that our approach will be exemplary for the investigation of other human genetic (skin) diseases.

• DFG Programme: Research Grants
• International Connection: Switzerland
• Co-Investigator: Professorin Dr. Leena Kaarina Bruckner-Tuderman