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

胆固醇代谢紊乱（包括其合成和运输）与许多疾病状态有关，包括神经退行性疾病、神经发育和金属健康障碍、代谢性疾病和微生物感染。此外，许多罕见疾病都表现出胆固醇代谢紊乱的特征。在英国，许多研究小组都对胆固醇代谢进行了研究，但很少有实验室专门专注于分析胆固醇转化为胆汁酸和类固醇的过程中所涉及的无数中间体。斯旺西大学医学院的生物医学质谱实验室就是这样一个实验室，从MRC中程设备基金获得的新型质谱（MS）设备将为英国的研究人员提供获取专业质谱设备、样品制备、数据分析及其解释方面的专家知识的资源。质谱是研究胆固醇代谢（胆固醇组学）的主要技术，当与液相色谱（LC）相结合时，适用于在复杂混合物中无偏鉴定和定量最多的代谢物。代谢物鉴定的安全性由正交数据提供，包括保留时间、准确的质量测量和碎片模式，在胆固醇代谢物的情况下，优选多级碎片（MSn）。最近加入ms工具箱的是ms成像（MSI），进一步增加了可用的生物成像技术。目前的建议是一个具有MSn和UVPD功能的高分辨率质谱仪器，可以与现有的LC-MS接口、高空间分辨率AP-MALDI-MSI和高灵敏度LESAplus-LC-MSI相结合。AP-MALDI源提供<10微米的空间分辨率，而LESAplus-LC-MSI源提供异构体分离，灵敏度为pg/mg。该仪器将成为mrc在英国的研究资源。新仪器将支持MRC涉及胆固醇代谢的几个关键战略优先领域的科学研究，包括：(1)神经科学和心理健康；(2)感染和免疫；(3)分子医学；(4)临床和转化研究；(5)全球健康。

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.