Investigating Rhomboid Regulation of ADAM17 in Psoriasis and Skin Biology

牛皮癣是一种常见的皮肤病，影响英国2%的人口。它看起来像红色凸起的皮肤上覆盖着银色的鳞片。它是由于皮肤的正常更换过程“加速”而发生的。它也会影响关节，引起炎症和不适。由于皮疹的外观和不适及瘙痒的症状，牛皮癣对患者的生活质量有重大影响。它与抑郁症和自杀念头有关。最近，研究表明，这些患者的心血管疾病（心脏病发作，高血压和中风）发病率较高。许多蛋白质被认为调节银屑病中皮肤的炎症和增殖。虽然有几种针对这些途径的治疗方法，但它们与许多副作用有关，如肝脏和肾脏损伤以及发生严重感染（包括结核病）的风险增加。我们的研究目的是寻找一种名为“ADAM 17”的蛋白质。这被认为是细胞内的“守门人”，控制许多其他蛋白质释放到血液中，这反过来又导致炎症和增殖。我们希望确定ADAM 17在银屑病中是如何调节的。我们的实验室处于最近两项发现的独特位置，这将有助于这项研究。我们已经确定了一个病人，其中ADAM 17是减少，因为基因突变。其次，我们分离了一组患者，其中ADAM 17增加与遗传性食管（食道）癌相关。他们有一个名为“iRHOM2”的基因突变。通过这两个患者的信息，我们可以探索iRHOM2是否调节ADAM17。使用这些患者的皮肤细胞，我们可以在实验室中创建模拟皮肤的三维模型。然后我们可以观察一些蛋白质和炎症标志物的释放。这可以与正常皮肤细胞进行比较，以了解这一途径对皮肤细胞行为的重要性。我们还希望直接检查银屑病患者的皮肤标本，并观察ADAM 17的活性以及它如何与包括iRHOM2在内的其他蛋白质相互作用。最后，我们将使用一种阻断ADAM17的药物，并将其应用于皮肤细胞，以观察阻断这一途径是否可以帮助银屑病细胞的行为与正常皮肤细胞更相似。虽然这些途径将在银屑病中进行研究，但所涉及的蛋白质在许多其他疾病中很重要。这些疾病包括炎症性肠道和关节疾病以及一些癌症。通过更详细地了解这一途径，我们希望为未来的药物开发确定急需的新靶点。

Psoriasis is a common skin condition, affecting 2% of the population in the UK. It appears as red raised patches of skin covered with silvery scales. It occurs as a result of "speeding up" of the usual replacement process of the skin. It can also affect the joints, causing inflammation and discomfort. Psoriasis can have a major impact on patients' quality of life because of the disfiguring appearance of the rash and symptoms of discomfort and itch. It has been associated with depression and suicidal thoughts. More recently, it has been shown that these patients have a higher incidence of cardiovascular disease (heart attacks, high blood pressure and stroke). Many proteins are thought to regulate the inflammation and proliferation of skin in psoriasis. Although there are several treatments available that target these pathways, they are associated with a number of side effects such as liver and kidney damage as well as an increased risk of developing serious infections including tuberculosis. Our research aims to look a protein called "ADAM17". This is thought to act as a "gate-keeper" within the cell, controlling the release of a number of other proteins into the blood, which in turn cause inflammation and proliferation. We hope to determine how ADAM 17 is regulated in psoriasis.Our laboratory is in the unique position of two recent discoveries, which will help this research. We have identified a patient in whom ADAM17 is reduced because of a genetic mutation. Secondly, we isolated a group of patients in whom ADAM 17 is increased in association with inherited oesophageal (gullet) cancer. They have a mutation in a gene called 'iRHOM2'. By using information from these two patients we can explore whether iRHOM2 regulates ADAM17.Using skin cells from these patients we can create three-dimensional models to mimic skin in the laboratory. We can then look at the release of a number of proteins and markers of inflammation. This can be compared with normal skin cells to understand the importance of this pathway on how skin cells behave. We also hope to directly examine skin specimens from patients with psoriasis and look at the activity of ADAM17 and how it interacts with other proteins including iRHOM2. Finally, we will use a drug which blocks ADAM17 and apply it to skin cells to see whether blocking this pathway could help psoriasis cells behave more similarly to normal skin cells. Although these pathways will be investigated in psoriasis, the proteins involved are important in a host of other diseases. These include inflammatory bowel and joint disease and a number of cancers. By understanding this pathway in more detail we hope to identify much needed new targets for future drug development.