Determining The Role of Photic and Non-Photic Time Cues in Resetting Lipid Circadian Rhythms in Humans

确定光和非光时间线索在重置人类脂质昼夜节律中的作用

• 批准号: 10675725
• 负责人: Shadab A Rahman
• 金额: $ 89.24万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675725
• 关键词: Acute; Address; Adult; Adverse effects; Animal Model; Area Under Curve; Biological Markers; Cardiometabolic Disease; Cardiovascular Diseases; Cholesterol; Chronic; Circadian Dysregulation; Circadian Rhythms; Clinical; Cues; Data; Development; Disease; Dyslipidemias; Eating; Evaluation; Event; Future; General Population; Goals; Health; High Prevalence; Hour; Human; Individual; Intervention; Jet Lag Syndrome; Knowledge; Light; Lipids; Measures; Mediating; Melatonin; Meta-Analysis; Metabolism; Patients; Peripheral; Phase; Phase response curves; Phototherapy; Physiological; Pilot Projects; Plasma; Population; Property; Public Health; Randomized; Randomized, Controlled Trials; Recommendation; Recurrence; Reporting; Resources; Risk; Role; Schedule; Sleep; Sleep Deprivation; Sleep disturbances; Stimulus; System; Therapeutic; Time; Time-restricted feeding; Triglycerides; Work; cardiometabolic risk; cardiometabolism; circadian; circadian regulation; design; experience; insight; lipid metabolism; lipidome; lipidomics; metabolomics; novel; pilot trial; primary outcome; public health relevance; response; shift work; social; therapeutic target; treatment strategy; young adult

Project Summary/Abstract Circadian rhythm disruption is experienced by patients with Circadian Rhythm Sleep-Wake Disorders and millions of shiftworkers worldwide, which may increase their risk of developing chronic health disorders including cardiovascular disease. Treatment of circadian rhythm disruption requires appropriately-timed intervention to either shift the circadian system earlier (advance) or later (delay). A Phase Response Curve (PRC) informs when to administer the intervention, without which the disruption may either be prolonged due to inadequate phase resetting or worsened due to shifting the system in the wrong direction. Currently, the field relies on the PRC for resetting the melatonin rhythm as guide to reset the entire circadian system, despite the fact that circadian rhythms are present in many other physiological features besides melatonin. Our preliminary data show that there are robust circadian rhythms in circulating levels of total cholesterol and triglyceride in healthy young individuals and that these rhythms can also be shifted. Our pilot studies further indicate that the timing of these lipid rhythms may be more responsive to shifts in the timing of meals rather than light exposure. We have constructed preliminary PRCs of these lipid rhythms in response to a combined stimulus of light exposure and meals distributed across the 24-h day and detected robust phase advances and delays. Moreover, the shifts in these lipid rhythms are larger than those for melatonin. We do not know, however, whether light exposure or meal timing is the primary time cue for resetting these lipid rhythms. Without this knowledge, developing a comprehensive treatment for circadian rhythm disruption of lipid rhythms that likely underlies the cardiometabolic consequences of shiftwork, will remain difficult. The objective of this proposal is to construct three PRCs that systematically examine the contribution of light and meal timing on resetting lipid circadian rhythms. Young healthy adults will be randomized to three conditions: (1) bright light + 12-h meal window, (2) dim light + 12-h meal window, and (3) dim light + 6.5-h meal window (time redistricted eating), each distributed across the 24-h day. The primary outcomes include phase resetting of lipid and melatonin circadian rhythms measured under each of the three conditions, and the area-under-the curve of the lipids during the 6.5-h time restricted eating. The aims of the study are to: (1) determine if light is the primary time cue for resetting melatonin but not lipid circadian rhythms, (2) determine if meal timing is the primary time cue for resetting lipid but not melatonin circadian rhythms, and (3) evaluate the acute effects of eating across the 24-h day on circulating lipid levels. Our work will be a comprehensive evaluation of how two daily events – light exposure and meals – synchronize lipid circadian rhythms in humans. We expect our analytic paradigm to be a foundational resource that can be extended to future studies of other peripheral systems under circadian regulation in humans, and have a positive public health impact by guiding therapeutic strategies for patients with circadian disruption and the population at large, many of whom experience recurrent circadian disruption due to irregular sleep-wake schedules.

项目概要/摘要 昼夜节律睡眠-觉醒障碍患者会经历昼夜节律紊乱， 全世界有数百万轮班工人，这可能会增加他们患慢性健康疾病的风险，包括 心血管疾病的治疗需要适当的定时干预。 提前（提前）或推迟（延迟）昼夜节律系统 相位响应曲线 (PRC) 会告知何时。 进行干预，否则中断可能会因阶段不足而延长 由于系统转向错误的方向而导致重置或恶化。目前，该领域依赖于中华人民共和国。 重置褪黑激素节律作为重置整个昼夜节律系统的指南，尽管事实上昼夜节律 除了褪黑激素之外，节律还存在于许多其他生理特征中。 健康年轻人的总胆固醇和甘油三酯的循环水平存在强大的昼夜节律 我们的试点研究进一步表明，这些节奏也可以改变。 血脂节律可能对进餐时间的变化比对光照的反应更敏感。 由这些脂质节律构建的初步 PRCs 响应光暴露和 一天 24 小时内的膳食分布，并检测到明显的相位提前和延迟。 然而，我们不知道这些脂质节律是否比褪黑激素更大。 进餐时间是重置这些血脂节律的主要时间线索。 针对脂质节律紊乱的综合治疗，这可能是心脏代谢的基础 轮班工作的后果仍将是困难的。该提案的目标是构建三个 PRC。 彻底研究了光照和进餐时间对重置脂质昼夜节律的影响。 健康成年人将被随机分配到三种条件：(1) 明亮光线 + 12 小时进餐窗口，(2) 昏暗光线 + 12 小时 进餐窗口，以及 (3) 昏暗灯光 + 6.5 小时进餐窗口（重新划分进餐时间），每个窗口分布在 24 小时内 主要结果包括在以下条件下测量的脂质和褪黑激素昼夜节律的阶段重置。 三种情况中的每一种，以及 6.5 小时限制进食期间的血脂曲线下面积。 该研究的目的是：（1）确定光是否是重置褪黑激素而不是脂质的主要时间线索 昼夜节律，(2) 确定进餐时间是否是重置脂质而不是褪黑激素的主要时间线索 昼夜节律，(3) 评估 24 小时内饮食对循环脂质水平的急性影响。 工作将全面评估两项日常事件——光照和进餐——如何同步脂质 我们期望我们的分析范式能够成为一种基础资源。 扩展到人类昼夜节律调节下的其他外周系统的未来研究，并具有积极的意义 通过指导昼夜节律紊乱患者和人群的治疗策略来影响公共健康 许多人由于不规则的睡眠-觉醒时间表而经常经历昼夜节律紊乱。