Sleeping sickness/cytokine effects on biological clock

昏睡病/细胞因子对生物钟的影响

• 批准号: 6555949
• 负责人: GENE D BLOCK
• 金额: $ 22.2万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-21 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6555949
• 关键词: Trypanosoma brucei rhodesiense; biological clocks; circadian rhythms; host organism interaction; interferon gamma; laboratory rat; neural information processing; parasite infection mechanism; pathologic process; suprachiasmatic nucleus; synapses; tissue /cell culture; trypanosomiasis; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Sleeping sickness, or African trypanosomiasis, is an infectious blood disease caused by the extracellular parasite Trypanosoma brucei (T. b.). The disease is characterized by a marked fragmentation of the sleep-wake cycle. For the proposed project, an experimental chronic rat model of sleeping sickness will be used to study the effects of a blood disease on the circadian system. Rats infected with T. b. display clear signs of a disturbed circadian regulation. These disturbances include a fragmented sleep-wake pattern, alterations in hormonal release, and a dysregulation of the intrinsic rhythmic activity in the suprachiasmatic nuclei (SCN), the principal pacemaker in the mammalian brain driving circadian rhythms. Experimental sleeping sickness therefore constitutes a unique model of a sleep disorder that can be used in order to study pathophysiological mechanisms mediating disturbances in the sleep-wake cycle. The mechanisms underlying these disturbances may involve certain inflammatory cytokines, which are released in high concentrations in the blood and expressed in the brain as a response to the infection. We will perform electrophysiological recordings in the SCN from trypanosome-infected rats to examine if experimental sleeping sickness alters the circadian SCN function in vivo and in pacemaker neurons in vitro. In addition, we will employ reporter gene technology to monitor alterations of the circadian expression of 'clock genes' in SCN neurons from rats with sleeping sickness, and if these alterations can be restored in the absence of trypanosome-derived molecules. Further, we will study how pro-inflammatory cytokines, in particular interferon-gamma and tumor necrosis factor-alpha, affect the neuronal activity, synaptic activity and 'clock gene' expression of SCN neurons to examine the impact of cytokines on circadian rhythms. Interferon-gamma is of particular interest since we have recently found that its receptor is expressed on neuronal elements in the ventrolateral SCN.

描述（由申请人提供）： 昏睡病或非洲锥虫病是一种由细胞外寄生虫布氏锥虫 (T. b.) 引起的传染性血液疾病。该疾病的特点是睡眠-觉醒周期明显破碎。对于拟议的项目，将使用实验性慢性昏睡病大鼠模型来研究血液疾病对昼夜节律系统的影响。感染 T. b. 的老鼠显示出昼夜节律紊乱的明显迹象。这些干扰包括支离破碎的睡眠-觉醒模式、激素释放的改变以及视交叉上核（SCN）内在节律活动的失调，视交叉上核是哺乳动物大脑中驱动昼夜节律的主要起搏器。因此，实验性昏睡病构成了睡眠障碍的独特模型，可用于研究介导睡眠-觉醒周期紊乱的病理生理机制。这些紊乱的机制可能涉及某些炎症细胞因子，这些细胞因子在血液中高浓度释放，并作为对感染的反应在大脑中表达。我们将对感染锥虫的大鼠的 SCN 进行电生理记录，以检查实验性昏睡病是否会改变体内和体外起搏神经元的昼夜节律 SCN 功能。此外，我们将采用报告基因技术来监测昏睡病大鼠SCN神经元中“时钟基因”昼夜节律表达的变化，以及这些变化是否可以在没有锥虫衍生分子的情况下恢复。此外，我们将研究促炎细胞因子，特别是干扰素-γ和肿瘤坏死因子-α，如何影响SCN神经元的神经元活动、突触活动和“时钟基因”表达，以检查细胞因子对昼夜节律的影响。干扰素-γ 特别令人感兴趣，因为我们最近发现其受体在腹外侧 SCN 的神经元元件上表达。