Optical approaches to delineate novel signalling pathways in skin blistering disease

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Recent advances in next generation sequencing have led to new insights into disease biology as well as opportunities for translational research. Through exome sequencing, we recently identified the first homozygous loss of function mutation in epidermal growth factor receptor (EGFR) in patients with inflammatory skin blistering. The EGFR signalling pathway regulates fundamental processes in cells including survival, migration, proliferation and secretion, in part through crosstalk with the integrin family of adhesion receptors. However, the mechanisms that control this crosstalk are largely unknown. This project will build on our novel findings to test the hypothesis that a balance between EGFR and integrin signalling plays a key role in maintaining skin homeostasis. Skin is a complex 3D tissue and analyzing contributions to tissue integrity from different endogenous cell populations is not possible without genetic manipulation. The use of 'caged' compounds, that are inert under native conditions but photolytically activated on exposure to certain light wavelengths, provides an excellent opportunity to manipulate endogenous protein behaviour within specific subsets of cells and study their role in tissue-like models. Chemical caging is a potentially powerful tool for translational research, but has been applied to a very limited subset of compounds/targets to date. We have established a collaboration with Tocris to develop selective optically-activated compounds to investigate the crosstalk between EGFR and integrin signaling within epidermal and stromal compartments of dermal equivalent 3D in vitro models. This project will provide excellent multidisciplinary training in translational cell biology and biological chemistry approaches to study mechanisms that control maintenance of human skin. Data arising from this study will provide important new tools for future studies of receptor signaling, as well as providing novel insight into fundamental regulatory pathways leading to human skin blistering diseases.