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.

项目摘要/摘要 昼夜节律节奏症患者经历了昼夜节律的破坏。 全球数以百万计的转移工人，这可能会增加他们患慢性健康障碍的风险 心血管疾病。昼夜节律中断的治疗需要适当定时的干预措施 更早地（延迟）移动昼夜节律系统。相响应曲线（PRC）信息 进行干预措施，没有该干预措施可能会延长由于相不足而延长 重置或因朝错误的方向移动系统而变质。目前，该领域依靠中国 重置褪黑激素节奏作为重置整个昼夜节律系统的指南，做昼夜节律的事实 除褪黑激素外，还有许多其他物理特征中存在节奏。我们的初步数据表明 健康的年轻人中的总胆固醇和甘油三酸酯的循环水平有强大的昼夜节律 个人，这些节奏也可以改变。我们的试点研究进一步表明这些时间的时机 脂质的节奏可能对饭菜时机的转移而不是轻度暴露可能更敏感。我们有 这些脂质节奏的初步PRC响应于光暴露和 用餐分布在24小时的一天中，并检测到稳健的相位进步和延迟。而且，转变 这些脂质节奏比褪黑激素大。但是，我们不知道光暴露还是 进餐时机是重置这些脂质节奏的主要时间提示。没有这些知识，开发一个 昼夜节律破坏脂质节奏的全面治疗可能是心脏代谢的基础 轮班工作的后果将保持困难。该提议的目的是建造三个中国 系统地检查光和餐时时间对重置脂质昼夜节律的贡献。年轻的 健康的成年人将被随机分为三个条件：（1）明亮的光 + 12小时餐窗，（2）昏暗的光 + 12-h 用餐窗口和（3）昏暗的光 + 6.5小时餐窗（重新分配饮食），每个餐厅分布在24小时 天。主要结果包括在以下测量的脂质和褪黑激素昼夜节律的相位重置 三个条件中的每一个以及在6.5小时内限制饮食中脂质的曲线的区域。 该研究的目的是：（1）确定光是重置褪黑激素但不是脂质的主要时间提示 昼夜节律，（2）确定进餐时间是否是重置脂质但不是褪黑激素的主要时间提示 昼夜节律和（3）评估整个24小时饮食对循环脂质水平的急性影响。我们的 工作将是对两个日常事件的全面评估 - 轻曝光和餐点 - 同步脂质 人类的昼夜节律。我们希望我们的分析范式成为一种基本资源 扩展到在人类昼夜节律调节下对其他外围系统的未来研究，并具有正面的研究 通过指导昼夜节律患者和人口的指导治疗策略来影响公共卫生的影响 大，其中许多人由于睡眠效果时间表不规则而经历了昼夜节律的反复中断。