MECHANISMS OF SLEEP RESPONSES TO VIRAL INFECTIONS

睡眠对病毒感染的反应机制

• 批准号: 2643547
• 负责人: JAMES Martin KRUEGER
• 金额: $ 31.4万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2643547
• 关键词: Orthomyxoviridae; Orthomyxoviridae disease; antibody neutralization test; cytokine; cytokine receptors; double stranded RNA; enzyme activity; gene expression; gene targeting; genetically modified animals; laboratory mouse; messenger RNA; molecular pathology; nitric oxide synthase; physiology; poly IC; sleep; virus RNA; virus replication

DESCRIPTION (Adapted from the applicant's abstract) Fatigue, excessive sleepiness, excess sleep and sleep disturbances are presenting symptoms in nearly all infectious diseases. The broad objective of this grant proposal is to characterize the molecular mechanisms responsible for changes in sleep induced by influenza virus. These investigators hypothesize that viral double-stranded (ds)RNA induces an upregulation of physiological somnogenic cytokines and de novo synthesis of other cytokines that amplify physiological sleep mechanisms, which include activation of nitric oxide synthase (NOS). Substantial preliminary data support this broad hypothesis. The model used for these sleep studies is A/PR/8/34-H1N1 influenza virus infection in the mouse. PR8 causes a pneumonitis accompanied by early onset of sleep responses. In the first Specific Aim, cytokine profiles induced by influenza virus or by the synthetic dsRNA,poly I:C in lungs will be compared. It is expected that the appearance of viral dsRNA will precede an upregulation of cytokine mRNA and that poly I:C will induce a similar pattern of cytokine expression. Further, the effects of antibody neutralization of viral dsRNA and the role of cytokine priming will be determined. Specific Aim #2 focuses on cytokine production in the brain and its involvement in viral-induced sleep responses. Three knockout strains of mice, each lacking receptors of one or more cytokines, will be infected and sleep responses determined. The ability of these mice to cope with the infectious challenge is expected to be compromised and their sleep responses blunted. Control mice similarly infected will be examined for cytokine mRNA expression in various area of brain. Brain expression of cytokines is expected to precede sleep responses and be localized to the hypothalamus and hippocampus. In Specific Aim #3 the role that NOS plays in viral-induced sleep responses will be determined. Three different NOS-knockout strains of mice (lacking NOS-1, -2 and -3, respectively) will be inoculated with influenza virus and sleep responses will be determined. The localization of the expression of NOS mRNAs in brain of similarly infected control mice will also be determined. It is anticipated that NOS-2 knockouts will be the more severely impaired mice and that viral-induced sleep responses will be attenuated in both NOS-1 and NOS-2 knockout mice. Viral-induced changes in NOS expression are expected to be localized in brain and be evident in lung tissue. The anticipated results will greatly aid our understanding of the molecular mechanisms involved in viral-induced sleep responses as well as physiological sleep mechanisms.

描述 （改编自申请人摘要）疲劳，过度嗜睡， 过度睡眠和睡眠障碍几乎在所有的 传染病这项拨款建议的主要目标是 描述负责睡眠变化的分子机制 由流感病毒引起。这些研究人员假设， 双链（ds）RNA诱导生理性致眠因子的上调， 细胞因子和其他细胞因子的从头合成， 生理睡眠机制，包括激活一氧化氮 合成酶（NOS）。大量的初步数据支持这一广泛的假设。 用于这些睡眠研究的模型是A/PR/8/34-H1N1流感病毒 感染小鼠。PR8导致肺炎伴早发 睡眠反应。在第一个特定目标中，由以下诱导的细胞因子谱： 流感病毒或合成的dsRNA，多聚I：C在肺中将 比较了预期病毒dsRNA的出现将先于病毒的出现。 细胞因子mRNA的上调和poly I：C将诱导类似的 细胞因子表达模式。此外，抗体的影响 病毒dsRNA的中和作用和细胞因子引发的作用将是 测定具体目标#2关注脑中细胞因子的产生， 与病毒引起的睡眠反应有关。三个敲除菌株 每只缺乏一种或多种细胞因子受体的小鼠将被感染， 睡眠反应确定。这些老鼠应对 感染性挑战预计会受到影响， 迟钝的。将检查类似感染的对照小鼠的细胞因子mRNA 在大脑的不同区域表达。细胞因子的脑表达是 预期在睡眠反应之前并定位于下丘脑， 海马体。在具体目标#3中，NOS在病毒诱导的细胞凋亡中所起的作用被证实。 将确定睡眠响应。三种不同的NOS敲除菌株 小鼠（分别缺乏NOS-1、NOS-2和NOS-3）将接种 流感病毒和睡眠反应将被确定。国产化 同样感染的对照小鼠脑中NOS mRNA的表达将 也要坚决。预计NOS-2淘汰赛将是更多的 严重受损的小鼠，病毒诱导的睡眠反应将 在NOS-1和NOS-2敲除小鼠中均减弱。病毒引起的变化 NOS的表达可能局限于脑组织，在肺组织中也有明显表达 组织.预期的结果将极大地帮助我们了解 涉及病毒诱导的睡眠反应的分子机制以及 生理睡眠机制