P3:VEGF Influences Keratinocyte-Immunocyte Interactions in Psoriasiform Dermatiti

P3：VEGF 影响银屑病样皮炎的角质细胞-免疫细胞相互作用

基本信息

批准号：
7928966
负责人：
Nicole Leanne Ward
金额：
$ 33.66万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7928966
关键词：
Abscess Acanthosis Aging Angiopoietins Back Blocking Antibodies Blood Vessels Calgranulin A Calgranulin B Caliber Cells Characteristics Chemotaxis Chronic Cutaneous DC101 Monoclonal Antibody Data Dendritic Cells Dermal Dermis Development Dichloromethylene Diphosphonate Disease E-Selectin Ear Edema Engineering Environment Epigenetic Process Etiology Exhibits Family Functional disorder Growth Factor Growth Factor Inhibition Homeostasis Hyperplasia Infiltration Inflammation Inflammatory Inflammatory Infiltrate Injury Lead Ligands Light Liposomes Literature Macrophage Activation Maintenance Mediating Mediation Messenger RNA Modeling Molecular Genetics Mus Myelogenous Myeloid Cell Activation Myeloid Cells National Institute of Arthritis and Musculoskeletal and Skin Diseases Outcome Measure Papillary Partner in relationship Patients Phenotype Play Principal Investigator Proteins Psoriasiform Dermatitis Psoriasis Receptor Protein-Tyrosine Kinases Recurrence Reporting Research Personnel Resolution Role S100 Proteins S100A8 gene S100A9 gene Signal Transduction Skin Skin Plaques Source Staining method Stains T-Cell Activation T-Lymphocyte Testing Tetracyclines Thick Tissues Transgenic Model Transgenic Organisms Translational Research Up-Regulation Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors aged angiogenesis cytokine inflammatory marker interleukin-23 keratinocyte macrophage member monocyte mouse model neutrophil new therapeutic target overexpression prevent programs promoter protein expression receptor skin disorder ward

项目摘要

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.

牛皮癣是一种常见的慢性皮肤疾病，其特征是复发性红斑皮肤斑块表现出表皮增生，炎性细胞的积累和乳头状皮肤异常脉管系统。研究血管特定生长因素的作用的研究表明，血管内皮生长因子（VEGF）和血管生成素家族对牛皮癣表型的发展和维护。我们已经设计了一条小鼠过表达血管生成蛋白酪氨酸激酶受体，角质形成细胞中的TIE2（KCS）和我们的初步数据表明这些小鼠具有牛皮癣状表型，包括内源性的显着增加 VEGF，存在棘皮，红细胞皮肤的存在，血管生成增加并增加炎症细胞浸润，特别是嗜中性粒细胞和髓样/单核细胞。我们假设KC特异性酪氨酸激酶受体的过表达通过增加的VEGF表达和激活导致KC增殖。皮肤变化导致血管生成增加，漏水和促炎的诱导蛋白质，S100A8/9，所有这些都增强了单核细胞/髓样细胞的募集，激活和炎症维持牛皮癣状表型。结合小鼠分子遗传方法和功能阻断抗体，我们将抑制VEGF信号传导，S100A8/A9表达或消除巨噬细胞并确定对表型发育和/或分辨率的影响。这这些研究的信息将提供对角色，互动和 VEGF，S100A8/A9和单核细胞/髓样细胞在发育中的重要性维护银屑病环境，并可能导致确定新的治疗靶标。