Investigating Rhomboid Regulation of ADAM17 in Psoriasis and Skin Biology

研究 ADAM17 在银屑病和皮肤生物学中的菱形调控

• 批准号: MR/K002740/1
• 负责人: Thiviyani Maruthappu
• 金额: $ 29.49万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK002740%2F1
• 关键词: Investigating; Rhomboid; Regulation; ADAM17; Psoriasis

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.

牛皮癣是一种常见的皮肤疾病，影响了英国2%的人口。它看起来像覆盖着银色鳞片的红色凸起的皮肤斑块。它是由于通常的皮肤替换过程“加速”而发生的。它还会影响关节，引起炎症和不适。牛皮癣会对患者的生活质量产生重大影响，因为它会出现皮疹、不适和瘙痒等症状。它与抑郁和自杀念头有关。最近的研究表明，这些病人患心血管疾病（心脏病、高血压和中风）的几率更高。许多蛋白质被认为在牛皮癣中调节皮肤的炎症和增殖。虽然有几种针对这些途径的可用治疗方法，但它们与许多副作用有关，例如肝脏和肾脏损害，以及发生包括结核病在内的严重感染的风险增加。我们的研究旨在研究一种名为ADAM17的蛋白质。这被认为是细胞内的“看门人”，控制许多其他蛋白质释放到血液中，进而引起炎症和增殖。我们希望确定adam17在牛皮癣中是如何被调节的。我们实验室最近有两项独特的发现，这将有助于这项研究。我们已经确定了一位由于基因突变而导致ADAM17减少的患者。其次，我们分离了一组与遗传性食管癌（食道癌）相关的adam17升高的患者。他们的iRHOM2基因发生了突变。通过使用这两个患者的信息，我们可以探索iRHOM2是否调节ADAM17。利用这些病人的皮肤细胞，我们可以创建三维模型来模拟实验室里的皮肤。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牛皮癣患者的皮肤标本，观察ADAM17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，看看阻断这一途径是否能帮助牛皮癣细胞表现得更像正常的皮肤细胞。虽然这些途径将在牛皮癣中进行研究，但所涉及的蛋白质在许多其他疾病中也很重要。这些疾病包括炎症性肠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。

项目成果

Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms.

• DOI: 10.1186/s13023-015-0346-2
• 发表时间: 2015-09-29
• 期刊: Orphanet journal of rare diseases
• 影响因子: 3.7
• 作者: Ellis A;Risk JM;Maruthappu T;Kelsell DP
• 通讯作者: Kelsell DP

Loss-of-function desmoplakin I and II mutations underlie dominant arrhythmogenic cardiomyopathy with a hair and skin phenotype.

• DOI: 10.1111/bjd.17388
• 发表时间: 2019-05
• 期刊: The British journal of dermatology
• 作者: Maruthappu T;Posafalvi A;Castelletti S;Delaney PJ;Syrris P;O'Toole EA;Green KJ;Elliott PM;Lambiase PD;Tinker A;McKenna WJ;Kelsell DP
• 通讯作者: Kelsell DP

Discovery in genetic skin disease: the impact of high throughput genetic technologies.

• DOI: 10.3390/genes5030615
• 发表时间: 2014-08-04
• 期刊: Genes
• 影响因子: 3.5
• 作者: Maruthappu T;Scott CA;Kelsell DP
• 通讯作者: Kelsell DP