SPECIFICITY IN REL SIGNALING IN DROSOPHILA IMMUNITY

描述（作者摘要）：我们有兴趣了解NFkB Rel 信号传导途径在先天免疫应答中受到调节。在哺乳动物中， NFkB被激活，以响应大量不同的刺激， 免疫反应，反过来又可以激活一系列令人印象深刻的靶基因。 多种配体及其特异性受体激活许多相同的 作用于Rel蛋白上游的信号传导组分。的数量 Rel信号通路之间共享的组分，特异性如何 在分子水平上实现的Rel信号传导？我们研究这个问题， 果蝇这使我们能够利用遗传学和基因组 序列信息来研究一个高度保守的信号通路， 有机体 该提案的具体目标是：1.为了鉴定新的基因， 通过基于图位克隆ird 1和ird 20的特异性Rel信号通路 基因.这两个基因是在免疫反应的遗传筛选中鉴定出来的 缺陷突变体这些基因是激活两种细胞所必需的。 三种已知的Rel蛋白通过克隆和鉴定这些基因，我们希望 了解它们是如何特定于一种途径而不是另一种途径的。2.到 了解一个IkB，仙人掌，如何能够不同地抑制多个Rel proteins.我们将测试是否不同形式的仙人掌优先关联 不同的Rel蛋白，如果仙人掌是差异磷酸化时， 它与不同的Rel蛋白复合。3.为了了解一个受体， Toll可以介导不同的致病信号。我们发现需要收费 对脂多糖和甘露聚糖的反应。我们将研究 其他Rel信号传导成分和其他Toll样受体，看看它们是否 LPS和/或甘露聚糖反应所需的。这可能会让我们了解 不同的途径可以使用相同的受体。这些研究将导致 更好地了解特定的Rel信号通路是如何调节的。 了解Rel信号传导应该有助于开发治疗方法， 炎症、内毒素休克和感染性疾病。

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.