DESCRIPTION (provided by applicant): One of the initial steps in the acute phase response in mammals is the release of signaling molecules, such as cytokines, by activated immune cells, including blood cells. These cytokines elicit distal effects on various organs including activation of the JAK/STAT pathway in the liver. It has been recently shown that, in Drosophila, septic injury triggers a response that is very similar to the mammalian acute phase response. Activated hemocytes (blood cells) produce a cytokine (Upd3), which distally activates the JAK/STAT pathway in the fat body, the functional equivalent of the mammalian liver. In order to further characterize the acute phase response in Drosophila it is specifically planned to 1) further characterize the components involved in JAK/STAT signaling upon immune challenge and 2) to analyze the regulation of the Upd3 cytokine expression in hemocytes. It is anticipated that addressing these aims will allow further understanding of the complex immune response in Drosophila and will likely lead to the discovery of evolutionary conserved components of innate immunity crucial to the response to invading microorganisms in mammals as well. In order to dissect the specific steps involved in acute phase response mediated by Upd3 and JAK/STAT signaling, many powerful approaches will be utilized. The Drosophila model system provides established genetic tools which permits both forward and reverse genetics. In particular, utilization of the GAL4/UAS system in combination with RNA interference hairpin constructs allows for silencing gene expression in a tissue-specific manner. These techniques in combination with established techniques in cell culture, quantitation of gene expression by molecular biology, and microscopy will enable us to broaden our understanding of acute phase response. Relevance: We have recently shown that the acute phase response, which refers to the complex integrated responses that occur in our body upon infection, has been conserved throughout evolution. We use the power of genetic strategies available in some insects, such as the fruit fly Drosophila melanogaster, to identify evolutionary conserved components relevant to the mammalian acute phase response.