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，涉及许多细胞组分、全身效应以及血管系统、巨噬细胞和其他血细胞类型的参与。炎症反应发生于损伤或感染，这些损伤或感染通常彼此偶联，进而产生促炎信号，包括细胞因子和胰高血糖素。炎症反应的全身激活对于愈合是必不可少的，但也与许多疾病相关。此外，寻找新的NSAID是一项重要的制药奋进。在这个提议中，提出了一个简单的，遗传上适合的，整个无脊椎动物模型的炎症反应。初步数据显示，果蝇幼虫表皮的损伤引起巨噬细胞中快速和系统性的NF（B）依赖性反应，并且这些细胞增加前列腺素（PGE 2）的产生。果蝇遗传学将允许快速鉴定调节这些反应的成分。目的是描述将表皮破裂与巨噬细胞的活化和巨噬细胞的反应联系起来的途径，包括产生胡萝卜素的机制。实验方法是全面的，以损伤诱导事件的几个分析为特色：巨噬细胞中NF（B活化的机制，巨噬细胞基因表达中NF（B依赖性变化，血液系统的造血和功能反应，以及前列腺素合成和信号传导。本研究产生的产品将是一种体内遗传模型，未来的遗传和药物筛选将适用于整个动物。

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.