Using Functional Genomics to Dissect Signaling Networks in Drosophila

信号转导是脊椎动物和无脊椎动物在发育和动态平衡过程中所必需的重要细胞过程。对果蝇和线虫等模式生物中信号通路的研究有助于我们理解信息是如何在每个高等生物中传递的。生物化学和遗传学研究已经确定了许多蛋白质组分，并组装了在物种之间保守的核心途径。信号模块似乎是可互换的，现在很明显，从遗传模型生物研究中获得的许多知识可以转移到对人类生理学的理解上。虽然已经确定了信号通路的许多组成部分，但对它们的转录靶标以及它们所影响的遗传网络知之甚少。该项目建议将功能基因组学和遗传学结合起来，作为一种策略来建立先天免疫反应期间潜在信号通路的电路模型。无脊椎动物和脊椎动物的免疫系统通过快速表达抗菌肽来应对微生物的挑战，作为对抗病原体的一线防御。Toll受体信号通路被激活，作为对病原体感染的主要反应，在果蝇和哺乳动物的宿主防御中似乎具有类似的作用。我们将使用免疫挑战果蝇的全基因组表达分析来建立一个在先天性免疫反应中激活或抑制的基因数据库。对Toll受体通路中突变的分析将有助于理解Toll样受体是如何实现信号特异性的。此外，还将利用时间进程研究对信号目标进行分类，以进行进一步的遗传和生化分析。这些研究应该确定应对微生物感染的先天免疫所需的新基因。

Signal transduction is an essential cellular process required during development and homeostasis in vertebrates and invertebrates. The study of signaling pathways in model organisms such as Drosophila and C. elegans has contributed significantly to our understanding of how information is transmitted every higher organism. Biochemical and genetic studies have identified many protein components and assembled core pathways that are conserved among species. Signaling modules appear to be interchangeable, and it is now clear that much of the knowledge obtained from studies in genetic model organisms is transferable to the understanding of human physiology. While many components of signaling pathways have been identified, there is rather little known about their transcriptional targets, and the genetic networks that they impinge on. This project proposes to combine functional genomics and genetics as a strategy to build models of the circuitry underlying signaling pathways during innate immune responses. Invertebrate and vertebrate immune systems respond to microbial challenges by rapid expression of antimicrobial peptides as an first-line defense against pathogens. Toll receptor signaling pathways are activated as a primary response to pathogenic infections and appear to have similar roles during host defense in Drosophila and mammals. We will use genome-wide expression analysis of immune challenged Drosophila to build a database of genes activated or repressed during innate immune responses. Analysis of mutants in the Toll receptor pathway should be instructive in understanding how signaling specificity is achieved by Toll-like receptors. Furthermore, time-course studies will be employed to classify signaling targets for further genetic and biochemical analysis. These studies should identify new genes that are required for innate immunity in response to microbial infections.