Psoriasis is a common, chronic skin disease characterized by recurrent erythematous skin plaques thatexhibit epidermal hyperplasia, inflammatory cell accumulation, and abnormalities of the papillary dermalvasculature. Studies examining the role of vascular specific growth factors have shown that members of thevascular endothelial growth factor (VEGF) and angiopoietin families contribute significantly to thedevelopment and maintenance of the psoriasis phenotype. We have engineered a line of mice thatoverexpress the angiopoietin tyrosine kinase receptor, Tie2 in keratinocytes (KCs), and our preliminary datasuggests that these mice have a psoriasiform phenotype, including significant increases in endogenousVEGF, presence of acanthotic, erythematous skin, increased angiogenesis, and increased inflammatory cellinfiltration, specifically neutrophils and myeloid/monocytic cells. We hypothesize that KC-specific tyrosinekinase receptor overexpression leads to KC proliferation, via increased VEGF expression and activation.This cutaneous change leads to increased angiogenesis, leaky vessels, and induction of the proinflammatoryprotein, S100A8/9, all of which enhance monocyte/myeloid cell recruitment, activation, and inflammationwhich maintain the psoriasiform phenotype. Using a combination of mouse molecular genetic approachesand function blocking antibodies, we will inhibit VEGF signaling, S100A8/A9 expression, or eliminatemacrophages and determine the effects on the development and/or resolution of the phenotype. Theinformation from these studies will provide further understanding about the roles, interactions, andsignificance of VEGF, S100A8/A9 and monocytic/myeloid cell activation in the development andmaintenance of the psoriatic environment and could result in the identification of new therapeutic targets.
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