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

虽然健康的人类皮肤可以处理每天短时间暴露在阳光下的问题，但许多人对太阳辐射的敏感性发生了变化，并出现了炎症性光毒性皮肤反应。这些光敏性疾病的情况从轻微到极其严重不等，可能会极大地影响患者的生活。虽然光敏性可能有遗传或免疫起源，但它也可能是对一些常用药物和食物成分的反应。目前，光敏性疾病的确切分子基础尚不清楚。人类皮肤依赖于专门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，我们建议探讨皮肤脂质的参与，统称为“皮肤脂质组”，以了解光敏性疾病的分子基础。我们计划使用临床材料，并调查当地的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类皮肤器官培养模型。我们将应用质谱靶向和非靶向脂质组学来研究参与太阳辐射引发的反应的脂质的类型和相对丰度，并将通过质谱脂质成像来探索它们的定位。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，我们将能够确定疾病的生物标志物特征，并支持专家治疗的决定。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，皮肤生物学，制药和临床研究方面的培训，包括处理脂质组学，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。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。这种伙伴关系将在化学-生物学-医学的界面提供独特的跨学科培训，并将为学生提供对现代学术界和制药行业职业生涯有价值的独特技能。

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.