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

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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.