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

虽然健康的人类皮肤可以在短时间内每天暴露在阳光下，但许多人对太阳辐射表现出不同的敏感性，并出现炎症性光毒性皮肤反应。这些光敏障碍可以是轻微的，也可以是极其严重的，这可能会极大地影响患者的生活。虽然光敏性可以有遗传或免疫来源，但它也可以对一些常用的药物和食品成分产生反应。目前，光敏性疾病的确切分子基础尚不清楚。人类皮肤依赖于专业的脂类来维持其结构和功能，已知局部产生的脂类介体参与皮肤的炎症和免疫反应，包括皮肤对阳光的反应。在这里，我们建议探索皮肤脂类的参与，统称为‘皮肤脂体’，以了解光敏性疾病的分子基础。我们计划使用临床材料，调查局部皮肤病和全身对太阳辐射的反应变化。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太阳辐射引发的反应中涉及的脂类的类型和相对丰度，并将通过质谱脂成像来探索它们的定位。研究结果将让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，通过比较不同光敏障碍患者皮肤和血液的变化，我们将能够识别疾病的生物标志物，并支持专家治疗的决定。这一点尤其重要，因为目前还没有针对这些疾病的有效治疗方法。这个多学科项目将提供生物化学、分析、皮肤生物学、制药学和临床研究方面的培训，包括处理由脂类组学、细胞和器官培养、脂类提取和质谱分析产生的大数据集。在安置期间，该学生将在产业合作伙伴的研究实验室工作，并接受尖端质谱学成像设备和软件方面的培训。该学生将加入曼彻斯特大学充满活力的研究环境，并将与我们的行业合作伙伴密切合作。这一合作伙伴关系将在化学-生物-医学的界面上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的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.