Investigating the cutaneous lipidome to understand the molecular basis of photosensitivity disorders

虽然健康的人类皮肤可以承受每天短时间的阳光照射，但许多人对太阳辐射的敏感性发生了变化，并出现了炎症性的光毒性皮肤反应。这些光敏性疾病可以从轻微到极端严重，可以极大地影响患者的生活。虽然光敏性可能有遗传或免疫的原因，但它也可能是对一些常用药物和食品成分的反应而产生的。目前，光敏性疾病的确切分子基础尚不清楚。人类皮肤依赖特殊的脂质来维持其结构和功能，已知局部产生的脂质介质参与皮肤炎症和免疫反应，包括皮肤对阳光的反应。在这里，我们建议探索皮肤脂质的参与，统称为“皮肤脂质组”，以了解光敏性疾病的分子基础。我们计划使用临床资料和调查局部皮肤和系统的变化发生在响应太阳辐射。除了进行临床研究外，我们还将使用细胞和人体皮肤器官培养模型。我们将应用质谱靶向和非靶向脂质组学来研究太阳辐射引发的反应中涉及的脂质类型和相对丰度，并将通过质谱脂质成像探索它们的定位。该研究结果将使我们详细了解人类皮肤容易发生异常炎症反应的属性。此外，我们相信，通过比较不同光敏性疾病患者的皮肤和血液变化，我们将能够识别疾病特征的生物标志物，并支持专科治疗的决策。这一点尤其重要，因为目前还没有有效的治疗方法。这个多学科项目将提供生物化学、分析学、皮肤生物学、药剂学和临床研究方面的培训，包括处理由脂质组学、细胞和器官培养、脂质提取和质谱分析产生的大型数据集。在实习期间，学生将在工业合作伙伴的研究实验室工作，并接受尖端质谱成像设备和软件的培训。该学生将加入曼彻斯特大学充满活力的研究环境，并将与我们的工业合作者密切合作。这种伙伴关系将提供独特的跨学科培训，在化学-生物-医学的界面，并将赋予学生独特的技能，有价值的职业生涯在现代学术界和制药行业。

While healthy human skin can handle daily exposure to sunlight for short periods of time, a large number of people show altered sensitivity to solar radiation and develop inflammatory phototoxic skin reactions. These photosensitivity disorders can vary from mild to extremely severe conditions that can greatly affect patients' lives. Although photosensitivity can have genetic or immune origins, it can also develop in response to 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' to understand the molecular basis of photosensitivity disorders. We plan to use clinical material and investigate local dermatological and systemic changes occurring in response to solar radiation. As well as conducting a clinical study, we will use cells and a human skin organ culture model. We will apply mass spectrometry targeted and untargeted lipidomics to study the type and relative abundance of lipids involved in reactions triggered by solar radiation, and will explore their localisation through mass spectrometry lipid imaging. The study outcomes will give us a detailed insight into the attributes of human skin prone to develop abnormal inflammatory reactions. Also, we believe that by comparing changes in the skin and blood of people with differing photosensitivity disorders we will be able to identify biomarkers characteristic of the disease and support decisions on specialist treatments. This is particularly important as, currently, there are no effective treatments for these conditions. This multidisciplinary project will provide training in biochemistry, analytics, skin biology, pharmaceutics and clinical research, 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 the industrial partners' 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. 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.