A Drosophila model for NFkB and prostaglandin dependent inflammatory response

描述(申请人提供)：哺乳动物的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。炎症发生在对通常相互耦合的损伤或感染的反应中，这反过来又会产生包括细胞因子和前列腺素在内的促炎信号。全身炎症反应的激活对愈合是必不可少的，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制药工作。在这项建议中，建议建立一种简单的、基因上可服从的、完整的无脊椎动物炎症反应模型。初步数据显示，果蝇幼虫表皮的损伤可引起巨噬细胞快速和系统的核因子(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。其目的是描绘将表皮破裂与巨噬细胞的激活和巨噬细胞的反应联系起来的途径，包括产生前列腺素的机制。实验方法是全面的，以几个损伤诱导事件的分析为特色：巨噬细胞中核因子(B)激活的机制，巨噬细胞基因表达中依赖于核因子(B)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。这项研究的结果将是一种活体遗传模型，利用该模型，未来的遗传和药物筛选将在整个动物中进行。 与公共卫生相关：人类的炎症反应可防止受伤和感染，但其调节失调可能是许多免疫和非免疫相关疾病的原因。对损伤的炎症反应的一个方面涉及巨噬细胞的快速激活和募集以及随后炎症前列腺素的产生，这一过程被非类固醇抗炎药抑制。我们已经能够为炎症反应的这些方面建立一个果蝇模型，其中损伤导致巨噬细胞中核因子(B)的全身性核转位和前列腺素的上调；所涉及的遗传路径的细节将通过标准的遗传分析来破译，包括未来对参与这一过程的基因的筛选和可能抑制其作用的药物。

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. PUBLIC HEALTH RELEVANCE: The human inflammatory response protects against injury and infection, but its dysregulation can be the cause of many immune and non-immune related disorders. One aspect of the inflammatory response to injury involves the rapid activation and recruitment of macrophages and the subsequent production of inflammatory prostaglandins, a process that is suppressed by the application of NSAIDs. We have been able to create a Drosophila model for these aspects of the inflammatory response, where injury causes systemic nuclear translocation of NF(B in macrophages and the up-regulation of prostaglandins; the details of the genetic pathways involved will be deciphered by standard genetic analyses, including future screening for genes involved in the process and drugs that might suppress their actions.