Interleukin-1: A promoter of slow wave sleep

Interleukin-1：慢波睡眠的促进者

• 批准号: 7983902
• 负责人: JAMES Martin KRUEGER
• 金额: $ 37.28万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-04-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7983902
• 关键词: Action Potentials; Address; Adenine Nucleotide Translocator 1; Adenosine; Adenosine A1 Receptor; Agonist; Anterior Hypothalamus; Anti-Inflammatory Agents; Anti-inflammatory; Area; Attenuated; Biochemical; Brain; Brain Pathology; Brain-Derived Neurotrophic Factor; CREB-binding protein; Catabolism; Cell Culture Techniques; Cells; Chronic; Data; Dependency; EGF gene; Electrocorticogram; Electroencephalogram; Encephalitis; Enzymes; Epidermal Growth Factor; Epilepsy; FOS gene; Family; Family member; Fatigue; Fluorescence; Fourier Transform; Gene Components; Gene Expression; Genes; IL1R1 gene; IL4 gene; Immune system; Impaired cognition; Impairment; In Vitro; Inflammation; Inflammation Process; Inflammatory; Interleukin-1; Interleukin-1 beta; Interleukin-13; Ipsilateral; Knock-out; Light; Link; Lipopolysaccharides; Literature; Measures; Mediating; Mediation; Metabolic syndrome; MicroRNAs; Modeling; Mus; NF-kappa B; Nerve Growth Factors; Neurobiology; Neuroglia; Neurons; Neurotransmitter Receptor; Nucleus solitarius; Pattern; Performance; Phenotype; Physiological; Play; Polymerase Chain Reaction; Preoptic Areas; Process; Production; Property; Proteins; Purines; Purinoceptor; REM Sleep; RNA; Regulation; Relative (related person); Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Transduction; Sleep; Sleep Apnea Syndromes; Sleep Deprivation; Sleep Disorders; Sleep disturbances; Slow-Wave Sleep; Somatosensory Cortex; Somatotropin-Releasing Hormone; Stimulus; Stroke; Symptoms; Synapses; Testing; Transgenic Mice; Translating; Traumatic Brain Injury; Tumor Necrosis Factor-alpha; Wakefulness; Work; anakinra; area striata; centromere protein F; cytokine; drug development; extracellular; human CREBBP protein; human SLC25A4 protein; immunoreactivity; in vitro Model; in vivo; indexing; member; neuronal patterning; neuropathology; neurotransmission; non rapid eye movement; practical application; prevent; promoter; public health relevance; purine; receptor; receptor expression; response; sleep regulation; transmission process

DESCRIPTION (provided by applicant): Many of the symptoms associated with sleep loss, e.g. fatigue, performance impairments, metabolic syndrome, chronic inflammation, sleepiness, etc; can be elicited by administration of interleukin-1 beta (IL1) or related cytokines or can be prevented by blocking them. Nevertheless, the regulation of the IL1 family in the brain is mostly undetermined. Recently a new brain-specific IL1 receptor accessory protein (IL1 AcPb) was identified. Although its function remains unknown preliminary data show that sleep deprivation enhances its cortical expression. The function for another IL1 family member, IL36 (formerly ILF7) has very recently (unpublished) been identified; IL36 inhibits several pro-inflammatory somnogenic cytokines including IL1, while simultaneously promoting expression of anti-inflammatory anti-somnogenic cytokines. In Aim 1, we determine the roles that IL1 AcPb and IL36 have in sleep regulation. For over 100 years it has been known that prolonged wakefulness (W) enhances brain production and release of sleep regulatory substances (SRSs). Nevertheless, the property of W that is responsible for enhanced SRS activity remains to be identified. In Aim 2, we investigate the hypothesis that ATP, released during neurotransmission, is a signal that provides a measure of prior W activity. Specifically, ATP is translated, via purine P2 receptors, into a longer lasting index of prior brain usage through release of cytokines such as IL1 from glia. Preliminary data indicate that ATP agonists promote sleep while ATP antagonists inhibit sleep and P2X7 receptor expression varies with sleep propensity. In Aim 2, we test our model, the ATP-cytokine-adenosine hypothesis, by using mice lacking key model component genes such as the P2X7 receptor. These mice, for example have attenuated sleep responses to sleep loss and the inflammatory stimulus, lipopolysaccharide. In Aim 3, we focus on activity-dependency of SRS gene expression and EEG delta power. We make use of the light-sensitive channelrhodopsin 2 (ChR2) gene by expressing it in cell cultures, then activating the cells with various patterns of light and determine SRS and model gene expressions. We also use ChR2- transgenic mice for in vivo controlled activation of cortical neurons and subsequent manifestations on the EEG. Anticipated results will provide mechanistic answers to questions of how inflammation alters sleep and how cellular activity is translated into SRS mechanisms. Results will have practical application to IL1- associated brain pathologies including inflammation-associated sleep disturbances occurring in sleep apnea and metabolic syndrome. PUBLIC HEALTH RELEVANCE: The roles that interleukin-1 (IL1) and IL1 family (IL1F) members have in inflammation-associated sleep disturbances and physiological sleep regulation are investigated. The involvement of a brain-specific IL1 receptor accessory protein and IL36 in sleep and brain-inflammation processes is determined. Further, ATP released during neurotransmission is posited to be part of the mechanism by which the brain tracks prior activity during wakefulness. We test the hypothesis that extracellular ATP, via purine type 2 receptors- mediates release of IL1 and other cytokines from glia and plays a key role sleep regulation and sleep responses to inflammatory signals. Finally, we test whether different patterns of cell activation change gene expression of IL1 and other components of the ATP-cytokine-adenosine hypothesis and whether different cell activation patterns differentially alter EEG delta power state-specifically. Results will have practical application to IL1-associated brain pathologies including inflammation-associated sleep disturbances occurring in sleep apnea and metabolic syndrome.

描述（由申请人提供）：许多与睡眠不足相关的症状，例如睡眠不足。疲劳、表现障碍、代谢综合征、慢性炎症、嗜睡等；可以通过施用白细胞介素 1 β (IL1) 或相关细胞因子来引发，也可以通过阻断它们来预防。然而，IL1 家族在大脑中的调节作用大多尚未确定。最近发现了一种新的大脑特异性 IL1 受体辅助蛋白 (IL1 AcPb)。尽管其功能仍不清楚，但初步数据表明睡眠剥夺会增强其皮质表达。另一位 IL1 家族成员 IL36（以前称为 ILF7）的功能最近（未发表）已被确定； IL36 抑制包括 IL1 在内的多种促炎性睡眠细胞因子，同时促进抗炎性抗睡眠细胞因子的表达。在目标 1 中，我们确定了 IL1 AcPb 和 IL36 在睡眠调节中的作用。 100 多年来，人们都知道，长时间的清醒 (W) 可以增强大脑生成和释放睡眠调节物质 (SRS)。然而，W 增强 SRS 活性的特性仍有待确定。在目标 2 中，我们研究了这样的假设：神经传递过程中释放的 ATP 是一种信号，可以测量先前的 W 活动。具体来说，ATP 通过嘌呤 P2 受体通过神经胶质细胞释放 IL1 等细胞因子，转化为先前大脑使用情况的更持久的指数。初步数据表明，ATP 激动剂促进睡眠，而 ATP 拮抗剂抑制睡眠，P2X7 受体表达随睡眠倾向而变化。在目标 2 中，我们通过使用缺乏 P2X7 受体等关键模型组成基因的小鼠来测试我们的模型，即 ATP-细胞因子-腺苷假说。例如，这些小鼠对睡眠不足和炎症刺激脂多糖的睡眠反应减弱。在目标 3 中，我们关注 SRS 基因表达和 EEG delta 功率的活动依赖性。我们通过在细胞培养物中表达光敏通道视紫红质 2 (ChR2) 基因来利用它，然后用各种光模式激活细胞并确定 SRS 和模型基因表达。我们还使用 ChR2 转基因小鼠体内控制皮质神经元的激活以及随后的脑电图表现。预期结果将为炎症如何改变睡眠以及细胞活动如何转化为 SRS 机制等问题提供机械答案。结果将实际应用于 IL1 相关的脑部病理学，包括睡眠呼吸暂停和代谢综合征中发生的炎症相关的睡眠障碍。 公共健康相关性：研究了白介素 1 (IL1) 和 IL1 家族 (IL1F) 成员在炎症相关睡眠障碍和生理睡眠调节中的作用。确定了大脑特异性 IL1 受体辅助蛋白和 IL36 在睡眠和大脑炎症过程中的参与。此外，神经传递过程中释放的 ATP 被认为是大脑在清醒期间跟踪先前活动的机制的一部分。我们检验了这样的假设：细胞外 ATP 通过 2 型嘌呤受体介导神经胶质细胞释放 IL1 和其他细胞因子，并在睡眠调节和睡眠对炎症信号的反应中发挥关键作用。最后，我们测试了不同的细胞激活模式是否会改变 IL1 和 ATP-细胞因子-腺苷假说的其他成分的基因表达，以及不同的细胞激活模式是否会差异性地改变 EEG delta 功率状态。结果将实际应用于 IL1 相关的脑部病理学，包括睡眠呼吸暂停和代谢综合征中发生的炎症相关的睡眠障碍。