Spatial Cholesterol Metabolism: A Mass Spectrometer for Better Diagnosis and Understanding of Disease

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Disturbed cholesterol metabolism (including its synthesis and transport) is linked to many disease states including neurodegenerative, neurodevelopmental and metal health disorders, metabolic disease and microbial infections. In addition, many rare diseases show features of disturbed cholesterol metabolism. Research in many groups in the UK embraces cholesterol metabolism, but there are few laboratories which specifically focus on the analysis of the myriad of intermediates involved in pathways transforming cholesterol to bile acids and steroids. The Biomedical Mass Spectrometry Laboratory in Swansea University Medical School is one such laboratory and with new mass spectrometry (MS) equipment from the MRC Mid-Range Equipment Fund will provide a resource for researcher in the UK to access specialist MS equipment, expert knowledge in sample preparation, data analysis and its interpretation. MS represents the primary technology in the study of cholesterol metabolism (cholesterolomics) and when combined with liquid chromatography (LC) is suitable for the unbiased identification and quantification of the greatest number of metabolites in a complex mixture. Security of metabolite identification is provided by orthogonal data including retention time, accurate mass measurement, and fragmentation patterns, preferably, in the case of cholesterol metabolites, multistage fragmentation (MSn). A recent addition to MS-tool box is MS-imaging (MSI) adding further to the available bioimaging technologies. The current proposal is for a high-resolution MS instrument with MSn and UVPD capabilities which can be combined with existing interfaces for LC-MS, high spatial-resolution AP-MALDI-MSI and high sensitivity LESAplus-LC-MSI already in Swansea. The AP-MALDI source offers <10 micrometer spatial resolution while LESAplus-LC-MSI provides isomer separation and with pg/mg sensitivity. The instrument will be a resource for MRC-remit research in the UK. The new instrument will underpin scientific research in several key strategic priority areas for MRC which involve cholesterol metabolism, including (1) neuroscience and mental health; (2) infection and immunity; (3) molecular medicine; (4) clinical and translational research; and (5) global health.