JAK/STAT signaling in Drosophila acute phase response

描述（由申请人提供）：在哺乳动物中，局部生理稳态紊乱（如脓毒性损伤）导致全身反应，称为急性期反应。这个过程的一个主要早期步骤是激活的免疫细胞（包括血细胞）释放信号分子，如细胞因子。在全身释放后，这些细胞因子激活各种器官的信号通路，包括肝脏中的JAK/STAT信号通路。这导致编码血清蛋白（如CRP）的靶基因被激活，从而导致这些急性期蛋白的血液浓度发生巨大变化。我们最近发现，败血性损伤在果蝇中引发了类似的急性期反应。我们已经证明细胞因子样分子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，在脓毒性损伤的反应中，活化的血细胞产生一种细胞因子Upd3，这是激活脂肪体中JAK/STAT通路所必需的，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（昆虫血液）中的小肽的基因。脂肪体中缺乏JAK/STAT信号的果蝇表现出免疫功能缺陷，包括吞噬和对李斯特菌等致病菌感染的抗性。我们的假设是，在脓毒性损伤后，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，随后释放JAK/STAT调节的效应物，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实验来进一步表征JAK/ stat调控的果蝇急性期反应。特别是，我们提出(1)识别导致脓毒性损伤的upd3血细胞激活的信号和信号通路，(2)表征JAK/STAT信号传导的各种成分，(3)识别和表征JAK/STAT调节的血细胞功能的效应物。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。我们在果蝇身上的研究可能有助于理解哺乳动物急性期反应的作用，这是一种显著的同稳态反应，在整个进化过程中显然是保守的。

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.