Optical approaches to delineate novel signalling pathways in skin blistering disease

描绘皮肤水疱疾病新信号通路的光学方法

• 批准号: 1808965
• 金额: --
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1808965
• 关键词: Optical; approaches; delineate; novel; signalling

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.

下一代测序的最新进展带来了对疾病生物学的新见解以及转化研究的机会。通过外显子组测序，我们最近在炎症性皮肤水疱患者中发现了表皮生长因子受体（EGFR）的第一个纯合功能丧失突变。 EGFR 信号通路部分通过与粘附受体整合素家族的串扰来调节细胞的基本过程，包括生存、迁移、增殖和分泌。然而，控制这种串扰的机制很大程度上是未知的。该项目将以我们的新发现为基础，检验 EGFR 和整合素信号传导之间的平衡在维持皮肤稳态中发挥关键作用的假设。皮肤是一种复杂的 3D 组织，如果不进行基因操作，就不可能分析不同内源细胞群对组织完整性的贡献。使用“笼中”化合物在天然条件下呈惰性，但在暴露于某些光波长时会被光解激活，为操纵特定细胞亚群内的内源蛋白质行为并研究它们在组织样模型中的作用提供了绝佳的机会。化学笼是转化研究的潜在强大工具，但迄今为止仅应用于非常有限的化合物/靶标子集。我们与 Tocris 建立了合作，开发选择性光激活化合物，以研究真皮等效 3D 体外模型的表皮和基质隔室中 EGFR 和整合素信号传导之间的串扰。该项目将提供转化细胞生物学和生物化学方法方面出色的多学科培训，以研究控制人类皮肤维护的机制。这项研究产生的数据将为未来受体信号传导的研究提供重要的新工具，并为导致人类皮肤起泡疾病的基本调控途径提供新的见解。