MOUSE MODEL OF EOSINOPHIL MEDIATED SKIN PATHOLOGY

嗜酸性粒细胞介导的皮肤病理学小鼠模型

• 批准号: 2467933
• 负责人: JAMES Joseph LEE
• 金额: $ 7.16万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2467933
• 关键词: cell adhesion molecules; cell migration; croton oil; eosinophil; genetically modified animals; interleukin 5; laboratory mouse; leukocyte activation /transformation; leukocyte adhesion molecules; pollen; selectins; skin hypersensitivity; skin irritation /irritant

DESCRIPTION (from the application): Interleukin 5 (IL-5) has been shown to be an important component of the cytokine regulatory network that controls peripheral eosinophil numbers and their recruitment/survivability at sites of inflammation. To understand better the role of IL-5 in cutaneous disease we have generated several transgenic lines of mice constitutively expressing a murine IL-5 gene in basal keratinocytes. Expression of IL-5 was restricted to this cell type using the regulatory elements of the human keratin-14 gene. The resulting mice appear to have a characteristic phenotype which includes a mild peripheral blood eosinophilia and a significant increase in resident cutaneous eosinophil infiltrates. Transgenic animals also show evidence of an increased frequency of hair-loss (alopecia). In addition, a subset of these animals spontaneously develop necrosing ulcerations of the skin. An important objective of this proposal is to augment ongoing studies of murine eosinophils by developing/characterizing a mouse model of eosinophil-mediated skin pathology to assess physiologically relevant effector functions in vivo. These effector functions will be tested in part through an evaluation of the transgenic mice as well as the response of these animals in established models of chemically-or allergen-induced inflammation. A long-term objective of this proposal is to integrate our molecular and mouse model approaches to understand eosinophil effector function with the downstream pathophysiological consequences of the recruitment and activation of this cell type in the skin. The specific aims of this proposal are: (1) The characterization of the molecular, cellular, and histopathological changes in a transgenic mouse line (NJ.692) expressing IL-5 in the skin using a human keratin-14 (K14) promoter (i.e., basal keratinocytes); (2) Evaluate and quantify the response of NJ.692 transgenic mice in experimental models of chemical- (Croton oil exposure) or allergen-(aerosolized ragweed pollen induced cutaneous type I hypersensitivity) induced inflammation as well as contact hypersensitivity reactions (Oxazolone exposure); (3) Characterization of the cell adhesion molecule (L-selectin, P-selectin, E-selectin, ICAM or VLA-4) dependence of eosinophil recruitment to the skin.

描述(来自应用程序)： 白介素5(IL-5)已被证明是血管紧张素转换酶的重要组成部分。 细胞因子调节网络，控制外周血嗜酸性粒细胞数量和 他们在炎症部位的招募/生存能力。要理解 更好的IL-5在皮肤病中的作用我们已经产生了几个 原始性表达小鼠IL-5基因的转基因小鼠品系 基底层角质形成细胞。IL-5的表达仅限于该细胞类型 利用人角蛋白-14基因的调控元件。由此产生的 小鼠似乎有一种特有的表型，包括轻度的 外周血嗜酸性粒细胞增多症和居民明显增多 皮肤嗜酸性粒细胞渗入。转基因动物也显示出 脱发(脱发)的频率增加。此外，一个子集 这些动物会自发地形成皮肤的坏死性溃疡。一个 这项建议的重要目标是加强正在进行的小鼠研究 通过建立/表征一种嗜酸性粒细胞的小鼠模型 嗜酸性粒细胞介导的皮肤病理学评估生理学相关性 效应器在体内发挥作用。这些效应器功能将进行部分测试 通过对转基因小鼠的评估以及对 这些动物在已建立的化学或过敏原诱导的模型中 发炎。这项提议的长期目标是将我们的 了解嗜酸性粒细胞效应器的分子和小鼠模型方法 与下游的病理生理后果有关的功能 这类细胞在皮肤中的招募和激活。具体目标 这一建议的主要内容是：(1)分子、细胞、 转基因小鼠株系(NJ.692)的组织病理学变化 使用人角蛋白-14(K14)启动子的皮肤中的IL-5(即，基础 角质形成细胞)；(2)评价和量化NJ.692转基因细胞的反应 小鼠化学-(巴豆油暴露)或 变应原-(豚草花粉雾化吸入诱导的I型皮肤 超敏反应)引起炎症和接触性超敏反应 反应(恶唑酮暴露)；(3)细胞黏附特性 细胞间黏附分子(L-选择素、P-选择素、E-选择素、细胞间黏附分子或VLA-4)的依赖性 嗜酸性粒细胞向皮肤募集。