Investigating the lipidome of human skin to understand the molecular basis of inflammatory phototoxic reactions

While healthy human skin can handle daily exposure to sunlight for short periods of time, a significant proportion of the population show altered sensitivity to solar radiation and develop inflammatory phototoxic skin reactions. These photosensitivity disorders vary from mild to extremely severe conditions that can greatly affect patients' lives. Although photosensitivity can have genetic or immune origins, it can also be mediated by a number of commonly used drugs and food ingredients. Currently, the exact molecular basis for photosensitivity disorders is not clearly understood.

Human skin depends on specialist lipids to maintain its structure and function, with locally produced lipid mediators known to be involved in cutaneous inflammatory and immune reactions, including the skin's response to sunlight. Here we propose to explore the involvement of skin lipids, collectively known as the 'cutaneous lipidome', in mechanisms underlying photosensitivity disorders.

We plan to use skin cells grown in culture and a human skin organotypic culture model to investigate changes occurring in response to solar radiation and drugs known to induce photosensitivity reactions. We will apply mass spectrometry using targeted and untargeted lipidomics techniques, to study the type and relative abundance of lipids involved in reactions triggered by solar radiation.

We will also explore the localisation of these changes through mass spectrometry lipid imaging. In parallel, we will investigate the molecular mechanisms underpinning the action of lipids that have been modified following their interaction with solar radiation and drugs, focusing on the activation of cell death pathways such as ferroptosis. The study outcomes will give us detailed insight into the molecular mechanism of sunlight-induced inflammation, and using advanced lipidomics technologies we will be able to identify biomarkers predicting the skin's reaction to drugs that can cause photosensitivity, leading to better clinical care.

This multidisciplinary project will provide training in biochemistry, bioanalytics, cell biology, skin biology and photobiology, including handling of large data sets generated by lipidomics, cell and organ culture, lipid extractions and mass spectrometry analyses. During their placement, the student will work at Waters' research laboratories and train in cutting edge mass spectrometry imaging equipment and software.

The student will join a vibrant research environment at the University of Manchester and will work closely with our industrial collaborators at Waters, Wilmslow. This partnership will provide unique interdisciplinary training at the interface of chemistry-biology-medicine and will give the student unique skills valuable for a career in modern academia and the pharmaceutical industry.