A Drosophila model for NFkB and prostaglandin dependent inflammatory response

描述（由申请人提供）：哺乳动物炎症反应是一个复杂的过程，涉及许多细胞成分、全身效应，并涉及血管系统、巨噬细胞和其他血细胞类型。炎症是对损伤或感染的反应，通常是相互耦合的，这反过来又产生促炎信号，包括细胞因子和前列腺素。全身炎症反应的激活对愈合至关重要，但也与许多疾病有关。此外，寻找新的非甾体抗炎药是一项重要的药学努力。在这个建议中，提出了一个简单的，遗传上可适应的，整个无脊椎动物模型的炎症反应的创建。初步数据显示，果蝇幼虫表皮损伤引起巨噬细胞快速和系统性的NF(b)依赖性反应，这些细胞增加前列腺素（PGE2）的产生。果蝇遗传学将允许快速识别调节这些反应的成分。目的是描述连接表皮破裂与巨噬细胞的激活和巨噬细胞的反应的途径，包括产生前列腺素的机制。实验方法是全面的，包括对损伤诱导事件的几种分析：巨噬细胞中NF(B)激活的机制，巨噬细胞基因表达中NF(B)依赖性的变化，血液系统的造血和功能反应，以及前列腺素的合成和信号传导。这项研究产生的产品将是一个体内遗传模型，未来的遗传和药物筛选将在整个动物中可行。

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.