A Drosophila model for NFkB and prostaglandin dependent inflammatory response

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DESCRIPTION (provided by applicant): The mammalian inflammatory response is a complex process that involves many cellular components, systemic effects, and involvement of the vascular system, macrophages and other blood cell types. Inflammation occurs in response to injury or infection that are often coupled with one another, which in turn generates proinflammatory signals including cytokines and prostaglandins. Systemic activation of inflammatory response is essential for healing but is also associated with many disorders. Furthermore, the search for new NSAIDs is an important pharmaceutical endeavor. In this proposal, the creation of a simple, genetically amenable, whole invertebrate animal model for inflammatory response is proposed. Preliminary data show that injury to the Drosophila larval epidermis causes a rapid and systemic NF(B-dependent response in macrophages and that these cells increase prostaglandin (PGE2) production. Drosophila genetics will allow for the rapid identification of components regulating these responses. The goal is to delineate the pathway that links the epidermal breach to the activation of the macrophages and the response of the macrophages, including the mechanism for generating prostaglandins. The experimental approach is comprehensive, featuring several analyses of injury- induced events: the mechanism of NF(B activation in macrophages, NF(B- dependent changes in macrophage gene expression, hematopoietic and functional responses of the blood system, and prostaglandin synthesis and signaling. The product resulting from this study will be an in vivo genetic model with which future genetic and drug screening will be feasible with whole animals.