P3:VEGF Influences Keratinocyte-Immunocyte Interactions in Psoriasiform Dermatiti

银屑病是一种常见的慢性皮肤病，其特征是皮肤反复出现红斑， 表现为表皮增生、炎性细胞聚集和乳头状真皮异常。 脉管系统。对血管特异性生长因子作用的研究表明， 血管内皮生长因子(VEGF)和血管生成素家族在 银屑病表型的发展和维持。我们已经培育了一系列老鼠， 在角质形成细胞中过表达血管生成素酪氨酸激酶受体Tie2和我们的初步数据 提示这些小鼠具有牛皮癣样表型，包括内源性激素显著增加 血管内皮生长因子，棘皮病，红斑性皮肤，血管生成增加，炎性细胞增多 浸润，特别是中性粒细胞和髓系/单核细胞。我们假设KC特异性酪氨酸 KK受体过表达通过增加血管内皮生长因子的表达和激活而导致KC的增殖。 这种皮肤变化导致血管生成增加，血管渗漏，并诱导促炎 S100A8/9蛋白，所有这些都能促进单核细胞/髓系细胞的募集、激活和炎症 保持牛皮癣样表型。使用小鼠分子遗传学方法的组合 和功能阻断抗体，我们会抑制血管内皮生长因子信号转导，S100A8/A9的表达，或消除 并确定对表型发育和/或分解的影响。这个 来自这些研究的信息将提供关于角色、交互和 血管内皮生长因子、S100A8/A9和单核/髓系细胞活化在卵巢癌发生、发展中的意义 维持牛皮癣的环境，并可能导致新的治疗靶点的确定。

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.