SPECIFICITY IN REL SIGNALING IN DROSOPHILA IMMUNITY

描述(作者摘要)：我们有兴趣了解NFkB如何发布 信号通路在先天免疫反应中受到调节。在哺乳动物身上， NFkB是在对大量不同的刺激做出反应时激活的 免疫反应，进而可以激活一系列令人印象深刻的目标基因。 多个配体和它们的特定受体激活许多相同的 作用于REL蛋白上游的信号成分。使用的数量 在REL信号通路之间共享的组件，其特异性如何 在分子水平上实现的REL信号？我们在#年研究这个问题。 果蝇。这使我们能够利用遗传学和基因组 序列信息用于研究高度保守的信号通路 有机体。 这项建议的具体目标是：1.确定新的基因所需的 基于MAP克隆ird1和ird20的特定REL信号通路 基因。这两个基因是在免疫反应的遗传筛查中确定的。 有缺陷的突变体。这些基因是激活其中两个所必需的 三种已知的Rel蛋白。通过克隆和鉴定这些基因，我们希望 理解它们是如何针对一条路径而不是另一条路径的。2.至 了解一个IKB，仙人掌，如何以不同的方式抑制多个REL 蛋白质。我们将测试不同形式的仙人掌是否优先关联 不同的REL蛋白，如果仙人掌在以下情况下被差异磷酸化 它与不同的Rel蛋白形成复合体。3.为了了解一个受体是如何， Toll可以介导不同的致病信号。我们发现通行费是必需的 对内毒素和甘露聚糖的反应。我们将研究突变的原因 其他REL信号组件和其他Toll样受体，看看它们是否 内毒素和/或甘露聚糖酶反应所需。这可能会让我们洞察到 不同的途径可以使用相同的受体。这些研究应该导致一个 更好地理解特定的REL信号通路是如何被调控的。 了解REL信号应有助于开发治疗 炎症、内毒素休克和传染病。

DESCRIPTION (authors abstract): We are interested in understanding how NFkB Rel signaling pathways are regulated in the innate immune response. In mammals, NFkB is activated in response to a great number of different stimuli in the immune response and in turn can activate an impressive range of target genes. Multiple ligands and their specific receptors activate many of the same signaling components that act upstream of the Rel proteins. With the number of components that are shared between Rel signaling pathways, how is specificity in Rel signaling achieved at the molecular level? We study this question in Drosophila. This allows us to take advantage of the genetics and the genome sequence information to study a highly conserved signaling pathway in a simpler organism. The specific aims of this proposal are: 1. To identify novel genes required for specific Rel signaling pathways by map-based cloning of the ird1 and ird20 genes. These two genes were identified in a genetic screen for immune response deficient mutants. These genes are necessary for activation of two out of the three known Rel proteins. By cloning and characterizing these genes, we hope to understand how they are specific for one pathway and not the other. 2. To understand how one IkB, Cactus, can differentially inhibit multiple Rel proteins. We will test if different forms of Cactus preferentially associate with different Rel proteins and if Cactus is differentially phosphorylated when it is complexed with different Rel proteins. 3. To understand how one receptor, Toll can mediate different pathogenic signals. We find that Toll is required for responses to lipopolysaccharide and mannans. We will look at mutations for other Rel signaling components and other Toll-like receptors to see if they are required for LPS and/or mannan responses. This may give insight to how different pathways can use the same receptor. These studies should lead to a better understanding of how specific Rel signaling pathways are regulated. Understanding Rel signaling should help in the development of therapies for inflammation, endotoxic shock and infectious diseases.