P3:VEGF Influences Keratinocyte-Immunocyte Interactions in Psoriasiform Dermatiti

银屑病是一种常见的慢性皮肤病，其特征是复发性皮肤斑块， 表现出表皮增生、炎性细胞积聚和乳头状真皮异常 脉管系统研究血管特异性生长因子的作用表明， 血管内皮生长因子（VEGF）和血管生成素家族在血管生成中起重要作用。 银屑病表型的发展和维持。我们设计了一系列小鼠， 在角质形成细胞（KCs）中过度表达血管生成素酪氨酸激酶受体Tie 2，我们的初步数据显示， 表明这些小鼠具有银屑病样表型，包括内源性 VEGF、棘皮、肥大皮肤的存在、血管生成增加和炎性细胞增加 浸润，特别是中性粒细胞和髓样/单核细胞。我们假设KC特异性酪氨酸 激酶受体过表达通过增加VEGF表达和活化导致KC增殖。 这种皮肤变化导致血管生成增加、血管渗漏和促炎性细胞因子的诱导。 蛋白质S100A8/9，所有这些都增强单核细胞/髓样细胞的募集、活化和炎症 其维持银屑病样表型。使用小鼠分子遗传学方法的组合 和功能阻断抗体，我们将抑制VEGF信号传导，S100A8/A9表达，或消除 巨噬细胞的细胞毒性，并确定对表型的发展和/或消退的影响。的 从这些研究中获得的信息将提供有关角色，相互作用和 VEGF、S100A8/A9和单核细胞/髓样细胞活化在肿瘤发生和发展中的意义 维持银屑病环境，并可能导致新的治疗靶点的鉴定。

Psoriasis is a common, chronic skin disease characterized by recurrent erythematous skin plaques that exhibit epidermal hyperplasia, inflammatory cell accumulation, and abnormalities of the papillary dermal vasculature. Studies examining the role of vascular specific growth factors have shown that members of the vascular endothelial growth factor (VEGF) and angiopoietin families contribute significantly to the development and maintenance of the psoriasis phenotype. We have engineered a line of mice that overexpress the angiopoietin tyrosine kinase receptor, Tie2 in keratinocytes (KCs), and our preliminary data suggests that these mice have a psoriasiform phenotype, including significant increases in endogenous VEGF, presence of acanthotic, erythematous skin, increased angiogenesis, and increased inflammatory cell infiltration, specifically neutrophils and myeloid/monocytic cells. We hypothesize that KC-specific tyrosine kinase 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 proinflammatory protein, S100A8/9, all of which enhance monocyte/myeloid cell recruitment, activation, and inflammation which maintain the psoriasiform phenotype. Using a combination of mouse molecular genetic approaches and function blocking antibodies, we will inhibit VEGF signaling, S100A8/A9 expression, or eliminate macrophages and determine the effects on the development and/or resolution of the phenotype. The information from these studies will provide further understanding about the roles, interactions, and significance of VEGF, S100A8/A9 and monocytic/myeloid cell activation in the development and maintenance of the psoriatic environment and could result in the identification of new therapeutic targets.