Cytokine signaling in Drosophila acute phase response

果蝇急性期反应中的细胞因子信号传导

• 批准号: 7561626
• 负责人: ANDREW W RASMUSSEN
• 金额: $ 2.44万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2009-08-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7561626
• 关键词: Acute-Phase Reaction; Address; Biological Models; Blood Cells; Cell Culture Techniques; Cells; Complex; Cytokine Signaling; Distal; Drosophila genus; Drosophila melanogaster; Event; Evolution; Fat Body; Gene Expression; Genetic; Hemocytes; Immune; Immune response; Infection; Injury; Insecta; Invaded; Lead; Liver; Mammals; Mediating; Microscopy; Modeling; Molecular Biology; Natural Immunity; Organ; Pathway interactions; Proteins; RNA Interference; Regulation; Signal Pathway; Signal Transduction; Signaling Molecule; Specificity; System; Techniques; Tissues; cytokine; insight; microorganism; positional cloning; research study; response; septic; tool

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.

描述（由申请人提供）：哺乳动物急性相响应的初始步骤之一是通过激活的免疫细胞（包括血细胞）释放信号分子，例如细胞因子。这些细胞因子会对各种器官产生远端影响，包括激活肝脏中的JAK/STAT途径。最近已经显示，在果蝇中，化粪池损伤会触发与哺乳动物急性期反应非常相似的反应。活化的血细胞（血细胞）产生细胞因子（UPD3），该因子远端激活脂肪体中的jak/stat途径，脂肪体（哺乳动物肝脏的功能相当）。为了进一步表征果蝇中的急性相响应，特别计划以1）进一步表征免疫攻击时JAK/STAT信号传导所涉及的成分，以及2）分析半细胞中UPD3细胞因子表达的调节。可以预料，解决这些目标将使果蝇中复杂的免疫反应进一步了解，并可能导致发现对哺乳动物侵入微生物的反应至关重要的先天免疫的进化保守成分。为了剖析upd3和jak/stat信号介导的急性相响应涉及的特定步骤，将使用许多强大的方法。果蝇模型系统提供了已建立的遗传工具，可允许前进和反向遗传学。特别是，GAL4/UAS系统与RNA干扰发夹构建体的利用允许以组织特异性方式沉默基因表达。这些技术与细胞培养中既定的技术结合使用，分子生物学对基因表达的定量以及显微镜将使我们能够扩大对急性期反应的理解。相关性：我们最近表明，急性相响应是指在感染后体内发生的复杂综合反应，在整个进化过程中一直保存。我们使用某些昆虫中可用的遗传策略的力量，例如果蝇果蝇甲那摩斯特，以鉴定与哺乳动物急性相反应相关的进化保守成分。