Investigating Rhomboid Regulation of ADAM17 in Psoriasis and Skin Biology

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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.