EB Simplex (EBS) is caused by dominant mutations in genes that make keratins K5 and K14. These two proteins form an extensive cytoskeleton which is necessary to protect the skin against mechanical and non-mechanical forms of stress. Severe keratin mutations lead to a collapse of the cytoskeleton and, ultimately, to skin fragility and skin blistering. So far, no successful therapy has been established for EBS.

Using a mouse model of EBS, Prof Magin’s group has recently demonstrated that the most prominent symptom of EBS, called cytolysis, is accompanied by a change in the gene expression programme of damaged skin cells, leading to a local inflammatory response. It is hypothesized that the pathology of EBS arises from skin fragility and a secondary, inflammatory response resulting from an altered keratin cytoskeleton. Knowledge of pathways leading to a stress response and to inflammation offers the basis for new therapeutic approaches. In fact, it was found that the application of the antibiotic, tetracycline, which can also suppress inflammation, has a beneficial effect on the condition of the group’s mouse model. In this proposal, the molecular basis for the stress response in EBS skin, and the mechanisms by which tetracycline and related antibiotics act, will be investigated.