Using Functional Genomics to Dissect Signaling Networks in Drosophila

信号转导是脊椎动物和无脊椎动物发育和体内平衡过程中必不可少的细胞过程。对模式生物（如果蝇和秀丽隐杆线虫）信号通路的研究对我们理解信息如何在高等生物中传递做出了重大贡献。生物化学和遗传研究已经确定了许多蛋白质成分和组装的核心途径在物种之间保守。信号模块似乎是可互换的，现在很清楚，从遗传模式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中。虽然已经确定了信号通路的许多组成部分，但对它们的转录靶点以及它们所影响的遗传网络知之甚少。本项目提出将功能基因组学和遗传学结合起来，建立先天免疫应答过程中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作为对抗病原体的第一线防御来应对微生物的挑战。Toll受体信号通路作为对致病性感染的主要反应而被激活，并且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先天免疫应答中激活或抑制的基因数据库。对Toll受体通路突变体的分析对于理解Toll样受体如何实现信号特异性具有指导意义。此外，时间过程研究将用于分类信号靶点，以进一步进行遗传和生化分析。这些研究应该确定对微生物感染的先天免疫反应所需的新基因。

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.