STAT6: A CRITICAL MEDIATOR OF ALLERGIC ASTHMA

STAT6：过敏性哮喘的关键介质

• 批准号: 6062395
• 负责人: DOUGLAS A KUPERMAN
• 金额: $ 3.24万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6062395
• 关键词: asthma; biological signal transduction; cytokine receptors; gene targeting; genetically modified animals; helper T lymphocyte; interleukin 4; laboratory mouse; respiratory hypersensitivity; transcription factor

DESCRIPTION Allergic asthma is characterized by airway hyper-reactivity (AHR), eosinophilia, and excessive mucus production. Evidence indicates that Th2 differentiated CD4+ T-cells mediate this phenomena. Recently, we have learned that IL-4 and IL-13 are the important products of Th2 cells which act on resident cells of the lung to induce AHR and mucus production in mice. Furthermore, IL-4 receptor alpha (IL-4r-alpha) deficient mice were protected of Th2 cells which act on resident cells of the lung to induce AHR and mucus production in mice. Furthermore, IL-4 receptor-alpha (IL-4r-alpha) deficient mice were protected from these effects. Therefore, the direction of future research has been narrowed to the role of IL-4-alpha mediated intracellular signaling in, as yet unidentified, resident cells of the lung. Ligation of IL-4r-alpha results in activation STAT6 and IRS2 intracellular signaling molecules. It is known that STAT6 is important in mediating most of the known effector functions of IL-4 and IL-13, including Th2 differentiation. Therefore, it is our hypothesis that STAT6 signaling in airway smooth muscle and epithelial cells is important in the development of AHR and mucus production. To address this hypothesis, we propose to expand the use of our STAT6. In particular, we will transfer Th2 cells to wildtype and STAT6-/- mice prior to antigen challenge and airway physiology measurements. Also, we will generate and similar phenotype airway smooth muscle and epithelial cell-specific STAT6 transgenic mice on a STAT6-/- mice prior to antigen challenge and airway physiology measurements. Also, we will generate and similarly phenotype airway smooth muscle and epithelial cell-specific STAT6 transgenic mice on a STAT6-/- genetic background.

描述 过敏性哮喘的特点是气道高反应性 (AHR)、嗜酸性粒细胞增多和粘液分泌过多。有证据表明 Th2 分化的 CD4+ T 细胞介导这种现象。最近，我们了解到IL-4和IL-13是Th2细胞的重要产物，它们作用于肺部常驻细胞，诱导小鼠AHR和粘液产生。此外，IL-4受体α（IL-4r-α）缺陷的小鼠受到Th2细胞的保护，Th2细胞作用于肺部常驻细胞，诱导小鼠产生AHR和粘液。此外，IL-4受体-α（IL-4r-α）缺陷的小鼠可以免受这些影响。因此，未来的研究方向已缩小到IL-4-α介导的细胞内信号传导在尚未鉴定的肺常驻细胞中的作用。 IL-4r-α 的连接导致 STAT6 和 IRS2 细胞内信号分子的激活。众所周知，STAT6 在介导大多数已知的 IL-4 和 IL-13 效应功能（包括 Th2 分化）方面发挥着重要作用。因此，我们假设气道平滑肌和上皮细胞中的 STAT6 信号传导在 AHR 和粘液产生的发展中很重要。为了解决这个假设，我们建议扩大 STAT6 的使用。特别是，我们将在抗原攻击和气道生理学测量之前将 Th2 细胞转移到野生型和 STAT6-/- 小鼠中。此外，在抗原攻击和气道生理学测量之前，我们将在 STAT6-/- 小鼠上产生类似表型的气道平滑肌和上皮细胞特异性 STAT6 转基因小鼠。此外，我们将在 STAT6-/- 遗传背景上产生类似表型的气道平滑肌和上皮细胞特异性 STAT6 转基因小鼠。