Interleukin-1: A promoter of slow wave sleep

描述（由申请人提供）：与睡眠丧失相关的许多症状，例如疲劳、行为障碍、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（IL 1）或相关细胞因子引起，或者可以通过阻断它们来预防。然而，IL 1家族在大脑中的调节大多是不确定的。最近发现了一种新的脑特异性白细胞介素1受体辅助蛋白（IL 1 AcPb）。虽然它的功能仍然未知，但初步数据表明，睡眠剥夺会增强其皮层表达。另一个IL 1家族成员IL 36（以前称为ILF 7）的功能最近（未发表）已被鉴定; IL 36抑制包括IL 1在内的几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。在目的1中，我们确定了IL 1 AcPb和IL 36在睡眠调节中的作用。100多年来，人们已经知道，长时间的觉醒（W）会增强大脑产生和释放睡眠调节物质（SRS）。然而，负责增强SRS活动的W的属性仍有待确定。在目标2中，我们研究的假设，ATP，在神经传递过程中释放，是一个信号，提供了一个衡量以前的W活动。具体而言，ATP通过嘌呤P2受体被翻译成更持久的先前大脑使用指数，通过从神经胶质释放细胞因子如IL 1。初步数据表明，ATP激动剂促进睡眠，而ATP拮抗剂抑制睡眠，P2 X7受体表达随睡眠倾向而变化。在目标2中，我们通过使用缺乏关键模型组分基因（如P2 X7受体）的小鼠来测试我们的模型，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，我们专注于SRS基因表达和EEG Δ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（ChR 2）基因来利用该基因，然后用各种模式的光激活细胞并确定SRS和模型基因表达。我们还使用ChR 2转基因小鼠在体内控制激活皮层神经元和随后的EEG表现。预期的结果将为炎症如何改变睡眠以及细胞活动如何转化为SRS机制的问题提供机械答案。结果将有实际应用IL 1相关的脑病理，包括炎症相关的睡眠障碍发生在睡眠呼吸暂停和代谢综合征。 公共卫生相关性：白细胞介素-1（IL-1）和IL-1家族（IL-1F）成员在炎症相关睡眠障碍和生理性睡眠调节中的作用进行了研究。确定了脑特异性IL 1受体辅助蛋白和IL 36参与睡眠和脑炎症过程。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。我们测试的假设，细胞外ATP，通过嘌呤2型受体介导的释放IL 1和其他细胞因子从神经胶质细胞，并发挥关键作用的睡眠调节和睡眠反应的炎症信号。最后，我们测试是否不同的细胞激活模式改变基因表达的IL-1和其他组件的ATP-细胞因子-腺苷假说，以及是否不同的细胞激活模式差异改变EEG δ功率状态特异性。结果将有实际应用IL 1相关的脑病理，包括炎症相关的睡眠障碍发生在睡眠呼吸暂停和代谢综合征。

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 The function for another IL1 family member, IL36 (formerly ILF7) has very recently (unpublished) been identified; IL36 inhibits several pro-inflammatory somnogenic cytokines including IL1, while simultaneously promoting expression of anti-inflammatory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.