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

项目描述：该项目将在现有的2D细胞培养工作的基础上，利用3D皮肤等量物和人皮肤外植体来研究SJS/TEN表皮脱离的分子发病机制。这是第一次将3D皮肤模型用于SJS/TEN研究。我们已经确定了一种新的分子途径，该途径在SJS/TEN患者皮肤中被促炎细胞因子肿瘤坏死因子α (TNF)上调，并在真皮/表皮连接的破坏中起关键作用，导致表皮脱离/起泡。使用SJS/TEN和健康的患者血清，以及活化的、分离的患者t细胞的条件培养基，您将处理暴露的角质形成细胞细胞系和3D皮肤等量物，并研究和表征TNF分子途径如何介导表皮脱离。此外，您将研究新的靶向治疗如何调节TNF的作用以减轻表皮脱离。该项目将有助于开发精准医学方法来治疗严重皮肤不良反应患者，并有可能利用针对特定致病机制的先进疗法。

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.