Sleep, Cytokines and Infection

睡眠、细胞因子和感染

基本信息

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
项目类别：
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

项目摘要

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）：感染会对心理健康产生负面影响。病人变得昏昏欲睡，出现认知缺陷和不适，并对社交和其他日常活动失去兴趣。感染期间中枢神经系统过程的显着变化是睡眠的改变。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大脑中这些细胞因子的作用介导的。首先，大量研究表明，IL-1、TNF 和 IL-6 在没有免疫挑战的情况下调节/调节生理睡眠。其次，已确定睡眠改变与这些相同细胞因子的增加相关的实验模型。 IL-1、TNF 和 IL-6 参与睡眠调节，以及这些细胞因子上调的感染期间发生的睡眠改变，表明感染引起的睡眠改变是由细胞因子介导的在大脑中。尽管似乎合理且基于经验证据，但尚未进行直接检验这一假设的研究。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小鼠感染模型，即盲肠结扎和穿刺诱发的败血症。我们提出的实验重点关注细胞因子（IL-1、TNF、IL-6）作为感染引起的睡眠改变的介质。我们将：1）确定感染改变睡眠的程度以及之前睡眠不足对感染反应的影响； 2) 量化感染期间大脑中细胞因子 mRNA 和蛋白质的变化； 3）回答“干扰大脑中细胞因子的作用是否会影响感染引起的睡眠改变？” IL-1、TNF 和 IL-6 在脓毒症中的外周作用已成为深入研究的主题，并且是已知的睡眠的中枢调节剂/调节剂。因此，有一个强大的概念框架可以研究睡眠和脓毒症之间的机制关系以及两个过程中涉及的介质。我们提供的初步数据证明急性外周感染后中枢神经系统功能的长期改变。我们展示了确定小鼠睡眠-觉醒行为的多个方面以及针对大脑中的细胞因子系统的能力。成功完成拟议的研究将为理解感染如何影响中枢神经系统功能提供至关重要的信息，睡眠的改变就证明了这一点。