Patterns of Sleep Restriction and Recovery: The Inflammatory Resolution Pathways

睡眠限制和恢复的模式：炎症消退途径

• 批准号: 9891863
• 负责人: MONIKA HAACK
• 金额: $ 85.12万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-15 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891863
• 关键词: Affect; Age; Aspirin; Back; Behavior; Biological Markers; Blood specimen; Data; Development; Dose; Down-Regulation; Experimental Models; Exposure to; Failure; Future; Goals; Homeostasis; Hospitals; Human; Individual; Inflammation; Inflammatory; Inflammatory Response; Interleukin-6; Interleukins; Laboratories; Lead; Length of Stay; Liquid Chromatography; Measures; Mediator of activation protein; Non-Steroidal Anti-Inflammatory Agents; Nonesterified Fatty Acids; Omega-3 Fatty Acids; Participant; Pathogenesis; Pathway interactions; Pattern; Pharmacology; Phase; Placebos; Play; Polysomnography; Process; Production; Recovery; Recurrence; Reporting; Resolution; Role; Series; Signal Transduction; Sleep; Sleep Deprivation; Sleep disturbances; Testing; Time; Up-Regulation; Woman; Work; base; chemokine; cytokine; design; disorder risk; experience; hospital utilization; human disease; inflammatory marker; lipid biosynthesis; lipid mediator; men; monocyte; novel; novel strategies; response; shift work; sleep behavior; sleep health; sleep pattern; sleep regulation; tandem mass spectrometry

PROJECT SUMMARY Low-grade or unresolved inflammation is involved in the pathogenesis of many human diseases. Common sleep patterns of restricting sleep during the work week and ‘catching up’ on sleep over the weekend lead to inflammatory upregulation that does not recover completely after the weekend. Goal of this proposal is to investigate, for the first time, inflammatory resolution pathways. Inflammatory resolution mediators, such as resolvins, are derived from omega-3 free fatty acids and actively ‘turn-off’ inflammation. Based on preliminary data from our lab, we hypothesize that common sleep restriction- recovery patterns disrupt inflammatory resolution pathways, making it difficult to return to inflammatory homeostasis. If true, pharmacologically increasing the body’s natural production of endogenous inflammatory resolution mediators may one day provide a way to reduce the detrimental inflammatory consequences of common sleep restriction-recovery patterns. The hypothesis will be tested using an experimental model that mimics common patterns of restricting sleep on week days and ‘catching up’ on sleep on the weekend. The proposal will further utilize the unique ability of low-dose aspirin, which – like no other non-steroidal anti-inflammatory drug – is able to activate inflammatory resolution pathways. Healthy women and men between the ages of 18 to 50 years will be tested under three 10-day long in-hospital stays, during which they will be exposed to control sleep or common patterns of sleep restriction-recovery. The two sleep restriction-recovery stays will be combined with preemptive administration of low-dose aspirin or placebo. Aim 1 will investigate whether exposure to commonly experienced sleep patterns of sleep restriction followed by recovery sleep will not only activate inflammatory (e.g., interleukin-6), but disrupt inflammatory resolution pathways (e.g., resolvins), as well. Aim 2 will test that activation of inflammatory resolution pathways by aspirin dampens the inflammatory response to sleep restriction. Aim 3 is target-unspecific and will profile a wide range of resolution lipid mediators using a liquid chromatography/tandem mass spectrometry (LC-MS/MS) platform, which may fuel the search of a biomarker to be used in the monitoring of sleep health. Targeting inflammatory resolution pathways could provide a novel, non-behavioral strategy to mitigate both inflammatory consequences and future disease risks in those undergoing periods of sleep restriction-recovery patterns – a behavior pattern that is unlikely to be eradicated in the near future, as changes in sleep are generally difficult to make and to maintain.

项目总结 低级别或未解决的炎症与许多人类疾病的发病机制有关。普普通通 在工作日限制睡眠和在周末补充睡眠的睡眠模式会导致 周末过后仍未完全恢复的炎性上调。 这项提议的目标是首次研究炎症消解途径。炎症性 分解调节剂，如解析素，源自omega-3游离脂肪酸，并能主动关闭。 发炎。根据我们实验室的初步数据，我们假设常见的睡眠限制- 恢复模式扰乱了炎症消解途径，使其难以恢复 炎症动态平衡。如果是真的，从药理上增加人体自然产生的 内源性炎症分解介质有朝一日可能会提供一种方法来减少有害的 常见睡眠限制-恢复模式的炎症后果。 这一假说将使用模拟常见限制模式的实验模型进行验证 工作日睡觉，周末补觉。该提案将进一步利用独特的 小剂量阿司匹林的能力，与其他任何非类固醇抗炎药不同，它能够激活 炎症消解途径。年龄在18到50岁之间的健康女性和男性将接受测试 在三个为期10天的住院期间，他们将暴露于控制睡眠或普通 睡眠受限--恢复的模式。两个睡眠限制-恢复停留将与 先发制人地服用小剂量阿司匹林或安慰剂。AIM 1将调查接触到 通常经历的睡眠模式，睡眠受限，然后是恢复睡眠，不仅会激活 炎症因子(如白介素6)，但也干扰炎症分解途径(如溶血素)。目标2 将测试阿司匹林激活炎症分解途径是否抑制炎症反应 睡眠限制。AIM 3是靶标非特异性的，将使用 LC-MS/MS(LC-MS/MS)平台，这可能会推动对 用于监测睡眠健康的生物标记物。 靶向炎症消解途径可以提供一种新的非行为策略来缓解这两种情况 睡眠受限-恢复期患者的炎症后果和未来疾病风险 模式-一种不太可能在不久的将来被根除的行为模式，就像睡眠的变化一样 通常很难制造和维护。