iRHOM mediated ADAM17 regulation in cutaneous disease and repair

Repair of the skin after wounding or chronic illness is a major clinical burden with age and infection being a particular problem. In this study, we have identified, from looking at families with inherited skin disease,two genes called iRHOM2 and ADAM17 generating proteins that interact with each other in skin. This was surprising as the two inherited skin conditions are quite distinct in their clinical presentation. The iRHOM2/ADAM17 interaction appears to play a very important role in the way the keratinocytes (the major cell of the top layer of skin called the epidermis) move and prevent infection after wounding. The increase in ADAM17 by iRHOM2 causes the keratinocytes to release growth factors and anti-inflammatory molecules that make the cells move quicker and prevent bacterial infection. Also it alters the way cells adhere to each other by modifying the cell adhesion machinery (in the desmosome) so they can also move and migrate over the wound much quicker. Thus we believe activation of this pathway may be an attractive target for improved chronic and acute cutaneous wound repair.

Cutaneous wound repair and infection are a major clinical burden . The focus of this proposal will be the investigation of the iRHOM2/ADAM17 pathway in desmosomal regulation and its role in re-epithelialisation during wound healing. From our disease gene discovery programme in monogenic skin and gastrointestinal syndromes, we have identified the first human knockouts for ADAM17 linked to a severe inflammatory skin and bowel phenotype and also "gain of function" mutations in the gene encoding iRHOM2 as the cause of Tylosis (skin disease and oesophageal cancer predisposition). Furthermore we show that iRHOM2 regulates ADAM17 processing and its "shedding" of key substrates including growth factors and pro-inflammatory cytokines. Utilising both patient keratinocytes and molecular biology tools, we demonstrate that iRHOM2/ADAM17 plays a key role in skin barrier maintenance, inflammation and migration. Thus activation of this pathway may be an attractive target for improved chronic and acute cutaneous wound repair.The three main approaches are as follows:
1) Localisation and function of WT and mutant iRHOMs in keratinocyte differentiation:This will investigate the localisation of iRHOMS in the epidermis, the effect of mutation on barrier formation and identify potential iRHOM interacting partners.
2) Dynamics of desmosome formation by iRHOM2: iRHOM2 regulates the sheddase ADAM17. One substrate is desmoglein2, a cadherin of the desmosomal adhesion complex. A number of studies are proposed to innvestiaget iRHOM2/ADAM17 in desmosomal regulation.
3) Human in vitro modelling of iRHOM2 driven wound healing: As our data indicates that TOC associated iRHOM2 mutations are linked with cell phenotypes associated with cutaneous wound healing, the role of iRHOM2 in wound healing will be assessed in a human acute wound model and 3D skin cultures modified genetically.

iRHOM2 is a relatively new molecule that is emerging as an important molecule in epithelial biology and cancer with key functions in regulation of growth factors and other ADAM17 mediated pathways including TNFalpha. iRHOM and ADAM17 are important molecules in epithelial biology with key functions in regulation of growth factors, endocytosis, inflammation, adhesion and apoptosis. Thus, this research will be of broad interest to dermatologists, immunologists, epithelial cell biologists, geneticists, cardiologists and the pharmaceutical industry.
The discovery of iRHOM2 mutations and then identifying its key regulatory role in regulating ADAM17 processing is likely to be of major interest to a number of researcher s and clinicians. For example:
1) Investigating ADAM17- regulation of growth factors and cyokines including TNFalpha in wound healing, normal epithelial homeostasis and inflammatory disease.
2) Its regulation of the desmosome may have implications in cardiocutaneous disease including ARVC.
3) Oesophageal cancer (predominantly squamous oesophageal cancer) is the sixth leading cause of cancer related deaths worldwide - there are 462,000 cases diagnosed with 386,000 patients dying each year. iRHOM2 is the first highly penetrant inherited oesophageal cancer gene and may represent a breakthrough for diagnosis, risk stratification and target development.
4) Cutaneous wound repair and the molecular mechanisms underlying re-epithelialisation and the prtective machinery top prevent bacterial adhesion and invasion.
The data produced as part of this study will be disseminated by talks at national and international conferences, as well as peer reviewed journals. The lead applicant has extensive experience in communicating and engaging with both academic and non-academic beneficiaries in molecular and cell biology.
The outcomes of this research may point other towards new therapeutic developments in the treatment of both acute and chronic wounds including from the pharmaceutical industry. Identification of novel therapeutic targets for cutaneous wound repair would represent a breakthrough in treating this complex and common condition. Exchanging this knowledge with our peers, patients and drug development organisations will be the key to ensuring the impact of our findings.
Should any of our research findings provide opportunities for commercial exploitation or application, we will work closely with Queen Mary University of London's Research and Development Office.Specifically, the Innovation Centre is part of Queen Marys ongoing commitment to its local community, and will provide high quality facilities needed for research commercialization. It is located in an area of east London that is developing into a Life Sciences cluster, centered around the Medical School and the Royal London Hospital. This network of world-class clinical, teaching and research resources offers exciting benefits for both healthcare research and the development/regeneration of the area.