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: 6055663
• 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/6055663
• 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）： 白细胞介素5（IL-5）已被证明是一个重要的组成部分， 控制外周嗜酸性粒细胞数量的细胞因子调节网络， 它们在炎症部位的募集/存活能力。 了解 更好的作用，IL-5在皮肤疾病，我们已经产生了几个 组成型表达鼠IL-5基因的转基因小鼠系， 基底角质形成细胞 IL-5的表达仅限于这种细胞类型 使用人角蛋白-14基因的调节元件。 所得 小鼠似乎具有特征性表型，包括轻度的 外周血嗜酸性粒细胞增多， 皮肤嗜酸性粒细胞浸润 转基因动物也显示出 脱发（脱发）的频率增加。 此外， 这些动物自发地产生皮肤坏死性溃疡。 一个 这项建议的一个重要目的是加强正在进行的鼠 通过开发/表征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，以评估生理相关性 效应子在体内起作用。 这些效应器的功能将被部分测试 通过对转基因小鼠的评估以及 这些动物在建立的化学或过敏原诱导的 炎症 这项建议的一个长期目标是将我们的 了解嗜酸性粒细胞效应子的分子和小鼠模型方法 功能与下游的病理生理后果， 招募和激活皮肤中的这种细胞类型。 具体目标 （1）分子，细胞， 转基因小鼠品系（NJ.692）中的组织病理学变化， 使用人角蛋白-14（K14）启动子（即，基底 （2）评估和量化NJ.692转基因细胞的应答; 小鼠在实验模型的化学-（巴豆油暴露）或 变应原-（雾化豚草花粉诱导皮肤I型 超敏反应）诱导的炎症以及接触性超敏反应 反应（恶唑酮暴露）;（3）细胞粘附的表征 分子（L-选择素、P-选择素、E-选择素、ICAM或VLA-4）依赖性 嗜酸性粒细胞向皮肤的募集。