Exploring the role of bioactive lipids in cell death pathways underpinning inflammatory skin disease

细胞死亡途径，如细胞凋亡、坏死性下垂或铁下垂，对于控制免疫反应、清除自身反应性免疫细胞、杀死感染细胞和癌细胞至关重要。重要的是，这些通路参与了慢性炎症性疾病的发病机制。生物活性脂类，如二十烷基类和神经酰胺，具有信号特性，并介导炎性和免疫反应。人类皮肤依赖生物活性脂类来维持其正确的结构和功能，有证据表明，它们的失调会导致炎症性皮肤病的发生。尽管生物活性脂类已被证明与细胞死亡途径有关，但它们在炎症性皮肤病发生的分子机制中的确切作用尚未得到充分的研究。破译细胞死亡途径和脂质之间的联系为发现新的炎症性疾病机制、开发治疗干预措施和促进精确医学方法提供了一个令人兴奋的机会。我们建议探索生物活性脂类和细胞死亡途径在炎症性皮肤病发展的分子机制中的作用，重点是银屑病。我们将使用人类皮肤和血细胞来充分了解不同隔室中的脂质介体疾病生物标志物。我们将激活细胞死亡途径，以探索基因和细胞因子的变化，并使用质谱脂组学将细胞脂质的变化与信号脂质介体产生联系起来。我们还将调查已知的靶向细胞死亡途径的候选药物对细胞脂体的影响。这项研究将导致发现细胞死亡途径的特异性生物标记物，阐明炎症性疾病发展的分子机制，并推进治疗干预。这一点特别重要，因为目前还没有获得许可的直接针对细胞死亡途径的疗法，尽管这些途径在包括牛皮癣在内的几种免疫介导性疾病的发病机制中发挥着重要作用。这一多学科项目将提供以下方面的培训：细胞生物学、免疫学、皮肤生物学、分析、药物和临床研究、基因组学和脂类组学产生的大数据集的处理、细胞和器官培养、脂质提取、质谱仪和遗传分析。这名学生还将在阿斯利康位于英国剑桥的研究实验室进行工业实习。该学生将加入曼彻斯特大学充满活力的研究环境，并将与我们在阿斯利康的行业合作伙伴密切合作。这一合作伙伴关系将在生物化学-生物-医学的界面上提供独特的跨学科培训，并将为学生提供对现代学术界和制药行业的职业生涯有价值的独特技能。

Cell death pathways such as apoptosis, necroptosis or ferroptosis, are critical for controlling immune responses, deleting self-reactive immune cells, and killing infected and cancer cells. Importantly, these pathways are involved in the pathogenesis of chronic inflammatory disease. Bioactive lipids such as the eicosanoids and ceramides, have signalling properties and mediate inflammatory and immune responses. Human skin depends on bioactive lipids to maintain its correct structure and function, and evidence suggests that their dysregulation leads to the development of inflammatory skin disease. Although bioactive lipids have been shown to be involved in cell death pathways, their exact contribution to the molecular mechanisms underpinning the development of inflammatory skin disease, are not fully explored. Deciphering the links between cell death pathways and lipids offers an exciting opportunity to discover new inflammatory disease mechanisms, develop therapeutic interventions and promote precision medicine approaches. We propose to explore the role of bioactive lipids and cell death pathways in the molecular mechanisms involved in the development of inflammatory skin disease, with emphasis on psoriasis. We will use human skin and blood cells to fully understand lipid mediator disease biomarkers in different compartments. We will activate cell death pathways to explore changes in genes and cytokines, and correlate changes in cellular lipids and signalling lipid mediator production using mass spectrometry lipidomics. We will also investigate the impact of drug candidates known to target cell death pathways on the cellular lipidome. The study will lead to the discovery of biomarkers specific to cell death pathways, elucidate the molecular mechanism of inflammatory disease development, and advance therapeutic interventions. This is of particular importance as there are currently no licensed therapeutics that directly target cell death pathways, although these play important roles in the pathogenesis of several immune-mediated diseases, including psoriasis. This multidisciplinary project will provide training in cell biology, immunology, skin biology, analytics, pharmaceutical and clinical research, handling of large data sets generated by genomics and lipidomics, cell and organ culture, lipid extractions, mass spectrometry and genetic analyses. The student will also undertake industrial placements at AstraZeneca's research laboratories at Cambridge, UK. The student will join a vibrant research environment at the University of Manchester and will work closely with our industrial collaborators at AstraZeneca. This partnership will provide unique interdisciplinary training at the interface of biological chemistry-biology-medicine and will give the student unique skills valuable for a career in modern academia and the pharmaceutical industry.