Keratinocyte gene expression in psoriasis and eczematous diseases
07 / 2005 - 10 / 2010
Psoriasis (PS) and atopic dermatitis (AD) are common inflammatory skin diseases that depend on genetic and environmental factors. Although the adaptive immune system has been implicated in these diseases, there is accumulating evidence that epithelium-derived factors and innate immune mechanisms might be driving the disease process. Our basic hypothesis is that PS and AD are caused and maintained by a vicious circle of cross talk between the immune system and the epidermal keratinocyte. Pharmacological intervention can therefore be directed at any point in this circle. Our lab has recently completed a comprehensive (20.000 genes) survey of gene expression in purified keratinocytes derived from skin of these patients. This resulted in a list of 181 genes whose expression is specifically and significantly altered in PS or AD. Many of these are predicted to be involved in inflammation and in abnormalities of keratinocyte growth control and differentiation. As such, these genes could be causally linked to the clinical symptoms of these diseases. NB: referenties verwijzen naar de lijst van Referenties en niet naar de lijst van Publikaties - Background - The overall, more distant aim is to translate data from large-scale expression studies into clinical applications. Specific aims are: (1) A number of differentially expressed genes from our transcriptomic screen will be examined in vitro, using epidermal cell populations derived from PS and AD patients. These are used to validate the expression data on patient material, at the mRNA or protein level, and to study the relevance of these genes with respect to control of epidermal proliferation. The aim of this part is to investigate the role of these genes in epidermal growth control, and to study their potential application as marker for germinative subpopulations (transit amplifying cells, stem cells). - Clinical relevance of the project - PS and AD are common diseases each affecting over 2% of the adult population. Current treatments are directed at interference with immune function (PS and AD), or with aberrant epidermal growth and differentiation (PS). Although the armamentarium of treatment modalities has been broadened over the last years, application of many of these is still limited by side effects or poor patient compliance. This project aims to discover new pharmacological targets based on functional genomics, and as such, it is a logical continuation of our NWO Genomics project.