STAT6: A CRITICAL MEDIATOR OF ALLERGIC ASTHMA

STAT6：过敏性哮喘的关键介质

• 批准号: 6363478
• 负责人: DOUGLAS A KUPERMAN
• 金额: $ 2.85万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6363478
• 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.

过敏性哮喘的特征是气道高反应性（AHR）、嗜酸性粒细胞增多和粘液分泌过多。有证据表明，Th 2分化的CD 4 + T细胞介导这种现象。最近，我们已经了解到IL-4和IL-13是Th 2细胞的重要产物，其作用于肺的驻留细胞以诱导小鼠中的AHR和粘液产生。此外，IL-4受体α（IL-4 r-a）缺陷型小鼠受到Th 2细胞的保护，Th 2细胞作用于肺的驻留细胞以诱导小鼠中的AHR和粘液产生。此外，IL-4受体-α（IL-4 r-alpha）缺陷小鼠受到保护，免受这些影响。因此，未来研究的方向已经缩小到IL-4-α介导的细胞内信号传导在尚未鉴定的肺驻留细胞中的作用。IL-4 r-a的连接导致STAT 6和IRS 2细胞内信号传导分子的活化。已知STAT 6在介导IL-4和IL-13的大多数已知效应子功能（包括Th 2分化）中是重要的。因此，我们假设气道平滑肌和上皮细胞中的STAT 6信号传导在AHR和粘液产生的发展中是重要的。为了解决这个假设，我们建议扩大我们的STAT 6的使用。特别地，我们将在抗原攻击和气道生理学测量之前将Th 2细胞转移到野生型和STAT 6-/-小鼠。此外，我们将在抗原攻击和气道生理学测量之前在STAT 6-/-小鼠上产生类似表型的气道平滑肌和上皮细胞特异性STAT 6转基因小鼠。此外，我们将在STAT 6-/-遗传背景下产生类似表型的气道平滑肌和上皮细胞特异性STAT 6转基因小鼠。