MOLECULAR ANALYSIS OF GENE REGULATION BY IL4R ALPHA

描述（改编自研究者摘要）：IL-4是一种重要的 免疫应答中的细胞因子，调节T细胞分化，B 细胞免疫球蛋白的产生和巨噬细胞的激活。这些 活性使IL-4在变应性疾病中起关键作用。IL-4作用 通过与IL-4受体（IL-4 R）结合， 共同伽玛链IL-4信号在靶细胞上的结果 可以被广泛地表征为生长或基因调节，活动， 其主要由IL-4 Ra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 STAT 6，其由IL-4 Ra基因调节结构域调节。我们的工作 重点是了解IL-4 Ra如何激活STAT 6， 这种激活作用对靶细胞信号传导的影响。第一特定 目的是从结构上表征IL-4 Ra基因调控结构域， 通过定位该结构域的最小STAT 6激活序列， 确定该序列的移动性，并确定 该序列在IL-4介导的基因表达中的基本性质。的 第二和第三个具体目标将决定STAT 6在IL-4- 1中的作用。 使用STAT 6-介导的肥大细胞和巨噬细胞的负信号传导 缺陷小鼠这些实验将使我们更好地了解 IL-4 Ra和STAT 6的结构-功能关系，以及 了解这些功能在细胞信号和过敏性疾病。

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.