Mechanotransduction in epidermolysis bullosa simplex

Keratinopathies are a group of hereditary cell fragility disorders caused by mutations in genes encoding for keratin proteins. The most studied disease is epidermolysis bullosa simplex (EBS). There is no effective therapy for EBS. EBS is predominantly autosomal dominant and linked to mutations in keratins 5 and 14. Mutant keratins disrupt the keratin cytoskeleton and place EBS keratinocytes in a state of stress, displaying mitogen-activated protein kinases activation, keratin aggregation, low cell adhesion and inability of cells to resist physical stresses. In patients this gives rise to severe skin blistering and wounding. As keratins are involved in cell adhesion to extracellular matrix proteins and to other cells, and at the same time are also inked to the nuclear lamina and nucleus, their function is fundamental to skin tissue homeostasis in general. Thus, cell adhesion proteins and their receptors constitute potential targets for the treatment of EBS. The goal of this project is to get an insight into the molecular basis of keratin related skin fragility, and the influence severe keratin mutations may have on mechanotransduction. To this end we will use a multidisciplinary approach involving biochemical isolation of proteins involved in adhesion, mass spectrometry, 2D and 3D engineered, EGFP labelled and/or induced pluripotent stem cell and tissue models with the aim to identify potential targets for EBS therapy that may allow us to circumvent the keratin mutation and regulate homeostasis through a different group of proteins.