Using Functional Genomics to Dissect Signaling Networks in Drosophila

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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.