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

探索生物活性脂质在炎症性皮肤病细胞死亡途径中的作用

• 批准号: 2899550
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2899550
• 关键词: Exploring; role; bioactive; lipids; cell

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.

细胞死亡途径，如凋亡、坏死性凋亡或铁凋亡，对于控制免疫反应、删除自身反应性免疫细胞以及杀死感染细胞和癌细胞至关重要。重要的是，这些途径参与慢性炎性疾病的发病机制。生物活性脂质如类二十烷酸和神经酰胺具有信号传导特性并介导炎症和免疫反应。人类皮肤依赖于生物活性脂质来维持其正确的结构和功能，有证据表明它们的失调导致炎症性皮肤病的发展。虽然生物活性脂质已被证明参与细胞死亡途径，但它们对炎症性皮肤病发展的分子机制的确切贡献尚未得到充分研究。破译细胞死亡途径和脂质之间的联系提供了一个令人兴奋的机会，以发现新的炎症性疾病机制，开发治疗干预措施和促进精准医学方法。我们建议探索生物活性脂质和细胞死亡途径在炎症性皮肤病（重点是银屑病）发展中的分子机制中的作用。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质疾病生物标志物。我们将激活细胞死亡途径来探索基因和细胞因子的变化，并使用质谱脂质组学将细胞脂质和信号脂质介质产生的变化关联起来。我们还将研究已知靶向细胞死亡途径的候选药物对细胞脂质体的影响。该研究将发现细胞死亡途径特异性的生物标志物，阐明炎症性疾病发展的分子机制，并推进治疗干预措施。这是特别重要的，因为目前没有直接靶向细胞死亡途径的许可治疗剂，尽管这些在几种免疫介导的疾病（包括银屑病）的发病机制中起重要作用。这个多学科项目将提供细胞生物学、免疫学、皮肤生物学、分析学、制药和临床研究、基因组学和脂质组学产生的大型数据集处理、细胞和器官培养、脂质提取、质谱和遗传分析等方面的培训。该学生还将在英国剑桥的阿斯利康研究实验室进行工业实习。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工业合作者密切合作。这种伙伴关系将在生物化学-生物学-医学的界面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职业生涯有价值的独特技能。