IL 3, IL 5, AND GM-CSF SIGNALING AND ASTHMA

描述(改编自申请人的摘要)：IL-3家族 包括IL-3、IL-5和GM-CSF在内的配体被认为与 哮喘的发病机制。IL-5和GM-CSF在高血压病患者中均有表达 慢性阻塞性肺疾病患者肺组织和分泌物中的水平 得了哮喘。这些细胞因子已被证明在 嗜酸性粒细胞、肥大细胞和几种 额外的促炎细胞。进一步使用IL-5治疗 特异性抗体已被证明可以阻断豚鼠的哮喘 模特。然而，这些细胞因子介导这些变化的机制 对其影响的描述一直很糟糕。最近，IL-3家族已经 被证明激活了两个不同但相关的信号通路 取决于目标细胞的分化状态。这条路 在未成熟的髓系细胞中激活使用一种信号转导因子 (STF-IL3a)，在生化和功能上与 信号传导因子(STF-IL3b)在成熟的髓系细胞中被激活。 这可能会提供第一个机械性的解释，解释为什么 细胞因子既可以是未成熟细胞的基本生长因子，也可以是 对更成熟的人有重要但明显的促炎作用 细胞(嗜酸性粒细胞和肥大细胞)。编码该成分的基因 最近克隆和发现了STF-IL3a的蛋白(p77和p80)。 是Stat 5的亚型，这是一种基于能力首次描述的因子 介导催乳素刺激酪蛋白基因的激活。这个 STF-IL-3b组分具有不同的分子量(P94和P96)， 但也似乎是Stat 5的异构体。作者假设 这四种蛋白质是两种不同的类似Stat 5的产物 基因。这些蛋白质的不同形式的产生可能是 在未成熟的细胞和成熟的细胞中进行调节。这样做的具体目的是 建议是：1.描述四个国家的不同作用5 IL-3配体家族信号传导中的异构体。2. 确定两个信号中的其他配基特定成分 由IL-3配体家族激活的级联反应。3.瞄准 Stat-5亚型与IL-3β受体的特异性相互作用 用于中断的链。

DESCRIPTION (Adapted from the applicant's abstract): The IL-3 family of ligands, which include IL-3, IL-5 and GM-CSF, have been implicated in the pathogenesis of asthma. Both IL-5 and GM-CSF are expressed at elevated levels in the pulmonary tissues and secretions of patients suffering from asthma. These cytokines have been shown to play a crucial role in the growth and activation of eosinophils, mast cells, and several additional pro-inflammatory cells. Furthermore treatment with IL-5 specific antibodies has been shown to block asthma in the guinea pig model. However, the mechanism by which these cytokines mediate these effects has been poorly characterized. Recently, the IL-3 family has been shown to activate two distinct, but related signaling pathways depending on the differentiation state of the target cell. The pathway activated in immature myeloid cells employs a signal transducing factor (STF-IL3a) that is biochemically and functionally distinct from the signal transducing factor (STF-IL3b) activated in mature myeloid cells. This may provide the first mechanistic explanation of how the same cytokine can be both an essential growth factor in immature cells and have an important but distinct pro-inflammatory effect on more mature cells (eosinophils and mast cells). The genes encoding the component proteins (p77 and p80) of STF-IL3a have recently been cloned and found to be isoforms of Stat 5, a factor first described based on the ability to mediate prolactin- stimulated activation of casein genes. The components of STF-IL-3b have distinct molecular weights (p94 and p96), but also appear to be isoforms of Stat 5. The authors have hypothesized that these four proteins are the products of two distinct Stat 5-like genes. The generation of different forms of these proteins may be regulated in immature vs. mature cells. The specific aims of this proposal are to: 1. Characterize the differential role of four Stat 5 isoforms in mediating signals for the IL-3 family of ligands. 2. Identify additional ligand specific components in the two signaling cascades activated by the IL-3 family of ligands. 3. Target the specific interactions between Stat 5 isoforms and the IL3beta receptor chain for interruption.