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

项目摘要/摘要 昼夜节律紊乱与昼夜节律睡眠-觉醒障碍 全世界数以百万计的轮班工人，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。昼夜节律紊乱的治疗需要适当的时机干预 或者提前(提前)或推迟(延迟)调整昼夜节律。相位响应曲线(PRC)通知何时 实施干预，如果没有干预，中断可能会因阶段不足而延长 由于将系统移向错误的方向而重置或恶化。目前，该油田依赖中国进行 重置褪黑激素节律作为重置整个昼夜节律系统的指南，尽管事实是 除了褪黑素，节律还存在于许多其他生理特征中。我们的初步数据显示， 健康青年的总胆固醇和甘油三酯循环水平有很强的昼夜节律。 这些节奏也是可以改变的。我们的试点研究进一步表明，这些措施的时机 与光照相比，血脂节律可能对进餐时间的变化更敏感。我们有 构建了这些脂质节律的初步PRC，以响应光暴露和 膳食分布在24小时内，并检测到强劲的阶段推进和延迟。此外，中国经济的转变 这些脂质节律比褪黑素的节律更大。然而，我们不知道光暴露或 进食时间是重置这些血脂节律的主要时间线索。如果没有这方面的知识，开发一个 可能导致心脏代谢紊乱的血脂节律昼夜节律紊乱的综合治疗 倒班工作的后果仍将是困难的。这项提议的目标是建立三个临立会 系统地研究光照和进餐时间对重置血脂昼夜节律的作用。年青的 健康成年人将被随机分为三种情况：(1)亮光12小时用餐窗口；(2)暗光12小时 用餐窗口，以及(3)昏暗的6.5小时用餐窗口(重新划分的用餐时间)，每个窗口分布在24小时内 天。主要结果包括脂质和褪黑激素昼夜节律的时相重置。 三种情况下的每一种情况，以及在6.5小时内血脂曲线下的面积都限制进食。 这项研究的目的是：(1)确定光是否是重置褪黑激素而不是脂类的主要时间线索 昼夜节律，(2)确定进食时间是否是重置血脂而不是褪黑激素的主要时间线索 昼夜节律，以及(3)评估24小时进食对循环血脂水平的急性影响。我们的 这项工作将对两种日常事件--光照和饮食--如何同步血脂进行全面评估 人类的昼夜节律。我们希望我们的分析范式成为一个基础性的资源，可以 扩展到未来对人类昼夜节律调节下的其他外周系统的研究，并具有积极的 通过指导昼夜节律紊乱患者的治疗策略对公共健康的影响 他们中的许多人由于不规律的睡眠-觉醒时间表而反复经历昼夜节律中断。

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.