MOLECULAR ANALYSIS OF GENE REGULATION BY IL4R ALPHA

描述(改编自《调查者摘要》)：IL-4是必不可少的 免疫反应中的细胞因子，调节T细胞分化 细胞免疫球蛋白的产生和巨噬细胞的激活。这些 活动使IL-4在过敏性疾病中发挥关键作用。白介素4受体 通过与IL-4受体(IL-4R)结合，由IL-4ra和 常见伽马链，GC。IL-4在靶细胞上的信号转导结果 可以广泛地描述为生长或基因调节，活动， 它们主要由IL-4ra的两个不同结构域控制。 许多IL-4诱导的基因表达事件需要激活 受IL-4ra基因调控结构域调控的STAT6。我们的工作 重点是了解IL-4ra如何激活STAT6及其结果 在靶细胞信号事件上的这种激活。第一个具体 目的是对IL-4ra基因调节域的结构特征进行研究， 通过映射该结构域的最小STAT6激活序列， 确定该序列的移动性，并确定 这一序列在IL-4介导的基因表达中的基本性质。这个 第二和第三个特定目标将决定STAT6在IL-4中的作用。 STAT6-6介导肥大细胞和巨噬细胞的负性信号 有缺陷的小鼠。这些实验将使我们更好地理解 IL-4ra和STAT6的结构与功能的关系 了解这些在细胞信号和过敏性疾病中的作用。

DESCRIPTION (Adapted from Investigator's Abstract): IL-4 is an essential cytokine in the immune response, regulating T cell differentiation, B cell immunoglobulin production, and the activation of macrophages. These activities give IL-4 a pivotal role in allergic disease. IL-4 acts through binding to the IL-4 receptor (IL-4R), composed of IL-4Ra and the common gamma chain, gc. The results of IL-4 signaling on target cells can be broadly characterized as growth or gene regulation, activities, which are predominantly controlled by two distinct domains of IL-4Ra. Many IL-4-induced gene expression events require the activation of STAT6, which is regulated by the IL-4Ra Gene Regulation Domain. Our work is focused on understanding how IL-4Ra activates STAT6 and the result of this activation on target cell signaling events. The first specific aim is to structurally characterize the IL-4Ra Gene Regulation Domain, through mapping of this domain's minimal STAT6 activation sequence, determining the mobility of this sequence, and ascertaining the essential nature of this sequence in IL-4-mediated gene expression. The second and third specific aims will determine the role of STAT6 in IL-4- mediated negative signaling of mast cells and macrophages using STAT6- deficient mice. These experiments will yield a greater understanding of the structure-function relationship if IL-4Ra and STAT6, and an understanding of these functions in cell signaling and allergic disease.