Functional characterisation of the major susceptibility locus (PSORS1) for cutaneous inflammation in psoriasis

Skin presents an essential barrier to environmental triggers capable of preventing challenge to the bodies natural defence mechanisms which includes a sophisticated immune surveillance network. Psoriasis, a life long skin disorder, is amongst a group of common conditions associated with chronic irritation and inflammation. Available evidence points to a fundamental defect in the capacity for barrier protection, dysregulation of the immune network or a combination of these through abnormal communication between skin and immune pathways. In order to develop new and effective therapies, a clear understanding of these processes and the fundamental defects that characterise the risk of developing psoriasis is now required. From a well defined region of the human genome, we have set out a series of studies designed to characterise the primary alterations that generate a very much increased risk disease development. Progress towards more effective ways to prevent or cure psoriasis would be expected to cut both in the short and long term, the heavy burden of chronic inflammation, and thus lead to a significant health and economic benefits compared to the present management of this disorder.

Psoriasis, a disorder characterised by chronic cutaneous inflammation is amongst the most significant health care problems in dermatological practice. Our group has been instrumental in the identification and delineation of the location of the major genetic risk factor for disease susceptibility, known as PSORS1 and in describing the critical role of T lymphocytes in disease pathogenesis. In order to correctly target therapeutic strategies that form part of our translational research programme, we now need to precisely identify a) the primary molecular defect underlying PSORS1 conferred susceptibility and b) the cellular types, dysregulation of which are key to disease development. Epithelial (keratinocytes) and lymphoid effector cells are prime candidates, as both are known, from our work in human and model systems, to be critical to disease expression and progression. However, we now need to establish the primacy of these cell types on a more physiological basis in the context of our previous genetic studies. To accomplish this we have established the following set of objectives. (1) We will generate a detailed map of transcriptional activity and regulators, across the PSORS1 major susceptibility genomic interval (~250kb) and relate these findings to underlying genetic variation, (2) we will perform functional studies of the two principle biological candidate genes within this region, namely the Class 1 immune recognition molecule, HLA C and CDSN encoding the epithelial junctional protein, corneodesmosin and (3) we will validate our studies through targeted mutagenesis of the PSORS 1 interval in an established in vivo model system. Taken together, these studies will deliver fundamental insights as to the aetiology of common chronic cutaneous inflammation and define the relationship between epithelial and lymphoid dysregulation that leads to the development of psoriasis.