Use of 3D skin models and patient-derived immune cells to elucidate the molecular mechanisms of skin detachment in severe drug-induced skin adverse re

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Project description: The project will expand on existing 2D cell-culture work by using 3D skin equivalents and human skin explants to investigate the molecular pathogenesis of epidermal detachment in SJS/TEN. This represents the first time that 3D skin models have been utilised for the purpose of SJS/TEN research. We have identified a novel molecular pathway which is up-regulated by the pro-inflammatory cytokine tumour necrosis factor alpha (TNF) in SJS/TEN patient skin and has a key role in the breakdown of the dermal/epidermal junction leading to epidermal detachment/ blistering. Using SJS/TEN and healthy patient serum, and conditioned media from activated, isolated patient T-cells you will treat exposed keratinocyte cell-lines and 3D skin-equivalents and investigate and characterise how the TNF molecular pathway mediates epidermal detachment. Furthermore, you will investigate how novel targeted therapies can modulate the effect of TNF to alleviate epidermal detachment. The project will help to develop precision medicine approaches to treating patients with sever cutaneous ADRs with the potential to utilise advanced therapies targeted to specific pathogenic mechanisms.