STAT6: A CRITICAL MEDIATOR OF ALLERGIC ASTHMA

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，Th2分化的CD4+ t细胞介导了这一现象。最近，我们了解到IL-4和IL-13是Th2细胞的重要产物，它们作用于小鼠肺常驻细胞诱导AHR和粘液产生。此外，IL-4受体α (il -4r- α)缺陷小鼠受到Th2细胞的保护，Th2细胞作用于肺驻留细胞，诱导小鼠AHR和粘液产生。此外，IL-4受体- α (il -4r- α)缺陷小鼠不受这些影响。因此，未来的研究方向已经缩小到il -4- α介导的细胞内信号在肺驻留细胞中的作用，但尚未确定。il -4r- α的连接导致细胞内信号分子STAT6和IRS2的激活。众所周知，STAT6在介导IL-4和IL-13的大多数已知效应功能中很重要，包括Th2分化。因此，我们的假设是，气道平滑肌和上皮细胞中的STAT6信号在AHR和粘液产生的发展中很重要。为了解决这一假设，我们建议扩大我们的STAT6的使用。特别是，我们将在抗原激发和气道生理测量之前将Th2细胞转移到野生型和STAT6-/-小鼠身上。此外，我们将在STAT6-/-小鼠上产生相似表型的气道平滑肌和上皮细胞特异性STAT6转基因小鼠，然后进行抗原激发和气道生理学测量。此外，我们将在STAT6-/-遗传背景下产生相似表型的气道平滑肌和上皮细胞特异性STAT6转基因小鼠。

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.