Sleep, Cytokines and Infection

睡眠、细胞因子和感染

• 批准号: 6952816
• 负责人: MARK R OPP
• 金额: $ 36.85万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-27 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6952816
• 关键词: brain stem; cysteine endopeptidases; electroencephalography; enzyme linked immunosorbent assay; genetically modified animals; hippocampus; hypothalamus; immune response; interleukin 1; interleukin 6; laboratory mouse; messenger RNA; nuclear factor kappa beta; posttranslational modifications; protease inhibitor; psychoneuroimmunology; septicemia; sleep; sleep deprivation; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Infection negatively impacts mental health. Sick individuals become lethargic, experience cognitive deficits and malaise, and lose interest in social contact and other usual daily activities. Prominent among the changes in CNS processes during infection are alterations in sleep. Cytokines, such as interleukin (IL)-1, tumor necrosis factor (TNF), and IL-6 are upregulated during infection. Two lines of evidence suggest that infection-induced alterations in sleep are mediated by actions of these cytokines in brain. First, numerous studies indicate IL-1, TNF, and IL-6 regulate/modulate physiological sleep in the absence of immune challenge. Second, experimental models for which alterations in sleep have been determined are associated with increases in these same cytokines. The involvement of IL-1, TNF, and IL-6 in the regulation of sleep, and the alterations in sleep that occur during infections in which these cytokines are upregulated, have led to suggestions that infection-induced alterations of sleep are mediated by cytokines in brain. Although plausible, and based on empirical evidence, studies to directly test this hypothesis have not been conducted. The fundamental goal of this project is to determine how acute infections alter sleep. To achieve this goal we will use a clinically relevant murine model of infection, sepsis induced by cecal ligation and puncture. We propose experiments that focus on cytokines (IL-1, TNF, IL-6) as mediators of infection-induced alterations in sleep. We will: 1) determine the extent infection alters sleep and the impact of prior sleep loss on responses to infection; 2) quantify alterations in cytokine mRNA and protein in brain during infection; and 3) answer the question "Does interfering with cytokine actions in brain impact infection-induced alterations in sleep?" IL-1, TNF, and IL-6 have been the subject of intense investigation with respect to their peripheral roles in sepsis, and are known central regulators/modulators of sleep. As such, there is a strong conceptual framework within which to investigate the mechanistic relationships between sleep and sepsis, and mediators implicated in both processes. We present preliminary data that demonstrate long-term alterations in CNS function following acute peripheral infection. We demonstrate our ability to determine multiple facets of sleep-wake behavior of mice and to target cytokine systems in brain. Successful completion of the proposed studies will provide information critical to understanding how infection impacts CNS function, as evidenced by alterations in sleep.

描述（由申请人提供）：感染对心理健康产生负面影响。患病的个体变得昏昏欲睡，经历认知缺陷和不适，并对社会接触和其他日常活动失去兴趣。在感染期间CNS过程的变化中，突出的是睡眠的改变。细胞因子，如白细胞介素（IL）-1，肿瘤坏死因子（TNF）和IL-6在感染过程中上调。两条证据表明，感染引起的睡眠改变是由这些细胞因子在大脑中的作用介导的。首先，许多研究表明IL-1、TNF和IL-6在没有免疫攻击的情况下调节/调节生理睡眠。其次，已经确定睡眠改变的实验模型与这些相同细胞因子的增加有关。IL-1、TNF和IL-6参与睡眠的调节，以及这些细胞因子在感染期间上调而发生的睡眠改变，已经导致了以下建议：感染诱导的睡眠改变是由脑中的细胞因子介导的。虽然似乎合理，并根据经验证据，研究，以直接测试这一假设尚未进行。该项目的基本目标是确定急性感染如何改变睡眠。为了实现这一目标，我们将使用临床相关的感染，盲肠结扎和穿刺诱导败血症的小鼠模型。我们提出的实验，专注于细胞因子（IL-1，TNF，IL-6）作为介质的感染引起的睡眠改变。我们将：1）确定感染改变睡眠的程度以及先前睡眠丧失对感染反应的影响; 2）量化感染期间脑中细胞因子mRNA和蛋白质的改变;以及3）回答问题“干扰脑中细胞因子作用是否影响感染诱导的睡眠改变？IL-1、TNF和IL-6在败血症中的外周作用一直是深入研究的主题，并且是已知的睡眠中枢调节剂/调节剂。因此，有一个强有力的概念框架，在其中调查睡眠和败血症之间的机械关系，以及在这两个过程中涉及的介质。我们目前的初步数据表明，长期的中枢神经系统功能的改变后，急性外周感染。我们证明了我们有能力确定小鼠睡眠-觉醒行为的多个方面，并靶向大脑中的细胞因子系统。成功完成拟议的研究将提供关键信息，以了解感染如何影响中枢神经系统功能，如睡眠的改变所证明的。