JAK/STAT signaling in Drosophila acute phase response

果蝇急性期反应中的 JAK/STAT 信号传导

• 批准号: 7893801
• 负责人: HERVE F AGAISSE
• 金额: $ 32.15万
• 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: 2007-08-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7893801
• 关键词: Acute-Phase Proteins; Acute-Phase Reaction; Address; Blood; Blood Cells; C-reactive protein; Cells; Code; Complex; Defect; Drosophila genome; Drosophila genus; Event; Evolution; Fat Body; Figs - dietary; Gene Expression Profile; Gene Targeting; Genes; Genetic; Genetic Screening; Hemocytes; Hemolymph; Homeostasis; IL6 gene; Immune; Immune response; Infection; Injury; Insecta; Janus kinase; Lead; Listeria; Liver; Mammals; Mediating; NF-kappa B; Natural Immunity; Organ; Pathway interactions; Peptides; Phagocytosis; Physiological; Process; RNA Interference; Regulation; Research Personnel; Resistance to infection; Role; Serum Proteins; Signal Pathway; Signal Transduction; Signaling Molecule; Specificity; Testing; Work; cell type; cytokine; design; fly; genetic analysis; immune function; in vivo; macrophage; novel; pathogenic bacteria; programs; receptor; research study; response; septic

DESCRIPTION (provided by applicant): In mammals, local disturbances of physiological homeostasis such as septic injury lead to a systemic response known as the acute phase response. A major early step in this process is the release of signaling molecules such as cytokines by activated immune cells, including blood cells. Upon systemic release, these cytokines activate signaling pathways in various organs, including the JAK/STAT signaling pathway in the liver. This leads to activation of target genes coding for serum proteins such as CRP, thus leading to dramatic changes in blood concentrations of these acute phase proteins. We have recently discovered that septic injury triggers a similar acute phase response in Drosophila. We have shown that the expression of the cytokine-like molecule Upd3 is activated in blood cells upon immune challenge. Our genetic analysis demonstrates that, in response to septic injury, activated blood cells produce a cytokine, Upd3, which is necessary to activate the JAK/STAT pathway in the fat body, an organ functionally equivalent to the mammalian liver. Activation of JAK/STAT signaling controls the expression of target genes, such as totA, a gene encoding a small peptide released into the hemolymph (insect blood). Flies deficient in JAK/STAT signaling in fat body display defects in immune functions including phagocytosis and resistance to infection with pathogenic bacteria, such as Listeria. Our hypothesis is that, upon septic injury, hemocytes sense the infection process and release signaling molecules that lead to activation of JAK/STAT signaling in the fat body and subsequent release of JAK/STAT-regulated effectors that, in return, assist hemocytes in accomplishing their immune functions. To test our hypothesis, we have designed a number of genetic experiments to further characterize the JAK/STAT-regulated acute phase response in Drosophila. In particular, we propose (1) to identify the signals and the signaling pathways leading to upd3 hemocyte activation in response to septic injury, (2) to characterize the various components involved in JAK/STAT signaling and (3) to identify and characterize the JAK/STAT-regulated effectors that modulate hemocyte functions. By taking advantage of powerful genetic strategies available in Drosophila, these studies will advance our understanding of complex integrated physiological responses involving various cell types, such as hemocytes and fat body cells and will likely uncover novel mechanisms related to innate immunity. Our work in Drosophila may help understand the role of the acute phase response in mammals, a remarkable homoeostatic response that has been apparently conserved throughout evolution.

描述(申请人提供)：在哺乳动物中，局部的生理动态平衡紊乱，如败血症损伤，会导致一种称为急性时相反应的全身反应。这一过程的一个主要早期步骤是激活的免疫细胞(包括血细胞)释放细胞因子等信号分子。当全身释放时，这些细胞因子激活不同器官的信号通路，包括肝脏的JAK/STAT信号通路。这会导致编码血清蛋白(如CRP)的靶基因被激活，从而导致这些急性时相蛋白的血液浓度发生显著变化。我们最近发现，败血症损伤会在果蝇身上触发类似的急性时相反应。我们已经证明了细胞因子样分子Upd3的表达在免疫攻击时在血细胞中被激活。我们的遗传分析表明，在对败血症损伤的反应中，激活的血细胞产生一种细胞因子Upd3，这是激活脂肪体中JAK/STAT途径所必需的，脂肪体是一个功能相当于哺乳动物肝脏的器官。JAK/STAT信号的激活控制靶基因的表达，如Tota，一种编码释放到血淋巴(昆虫血)中的小肽的基因。脂肪体内JAK/STAT信号缺陷的果蝇表现出免疫功能缺陷，包括吞噬功能和对李斯特菌等病原菌感染的抵抗力。我们的假设是，在败血症损伤后，血细胞感知感染过程并释放信号分子，导致脂肪体中JAK/STAT信号的激活，随后JAK/STAT调节的效应器的释放，反过来，帮助血细胞完成其免疫功能。为了验证我们的假设，我们设计了一些遗传学实验，以进一步表征JAK/STAT调节的果蝇急性时相反应。特别是，我们建议(1)确定败血症损伤后导致UPD3血细胞激活的信号和信号通路，(2)鉴定参与JAK/STAT信号转导的各种成分，以及(3)鉴定和表征JAK/STAT调节的调节血细胞功能的效应器。通过利用果蝇强大的遗传策略，这些研究将促进我们对涉及各种细胞类型(如血细胞和脂肪体细胞)的复杂综合生理反应的理解，并可能揭示与先天免疫相关的新机制。我们在果蝇上的工作可能有助于理解哺乳动物的急性期反应的作用，这是一种显著的自稳反应，显然在整个进化过程中都是保守的。