Biomarkers and Altered Metabolic Pathways during Sleep Loss and Circadian Disruption

项目摘要/摘要 约有5000万至7000万美国人患有睡眠和觉醒障碍，超过35%的美国人 每晚睡眠时间少于推荐的7小时。此外，劳动力中约20%的成年人是倒班- 因此有更高的昼夜节律失调的风险(即在生物日和 在生物体之夜的清醒)。与睡眠不足和昼夜节律有关的健康问题 失调包括炎症、抑郁和焦虑、滥用药物、胰岛素敏感性降低、糖尿病、 还有肥胖症。虽然睡眠对整体健康的贡献得到了很好的认可，但许多初级保健提供者失败了 诊断或识别睡眠和昼夜节律紊乱，估计显示未诊断的睡眠紊乱更多 比确诊的睡眠障碍更普遍。目前，还没有反映整体睡眠和昼夜节律健康的临床生物标志物 是存在的。开发这样的生物标志物有可能：1)提高对睡眠和昼夜节律紊乱的诊断； 2)确定导致心脏代谢性疾病风险增加的生化机制 睡眠不足和昼夜节律失调；以及3)提供基于睡眠和昼夜节律的新对策。 长期来看，睡眠和昼夜节律健康的生物标志物也可以支持个性化的 医学，部分是通过确定最有可能从基于睡眠和昼夜节律的干预中受益的个人。 K01的总体目标是识别睡眠不足和昼夜节律失调的生物标记物，并评估 睡眠时间增加对这些生物标志物的影响。我会用之前完成的两个NIH的样本- 资助基于实验室的方案以确定睡眠不足和昼夜节律的假定生物标记物 使用血浆代谢组学和蛋白质组学进行错位。我还将评估血浆代谢组和胰岛素 一项为期四周的试验的敏感性，该试验将夜间睡眠持续时间增加到推荐的≥7小时睡眠/晚上 以确定我识别的生物标记物是否可以区分这些人 基线睡眠不足和睡眠时间增加后，如果增加睡眠时间可以改善胰岛素敏感性。 该奖项将在四个领域提供关键培训：1)生物信息学；2)组学；3)临床转换睡眠和 昼夜节律研究和干预；以及4)专业发展，并将提供必要的初步 NIH R01的数据，以帮助我启动一个独立的研究计划。拟议的结果支持 2011年美国国立卫生研究院睡眠障碍研究计划“使睡眠和昼夜节律研究培训在 交叉领域，加快发现步伐，并将增强疗法从BASE转换为 从床边到社区“。

PROJECT SUMMARY/ABSTRACT Approximately 50-70 million Americans suffer from sleep and wakefulness disorders and over 35% of Americans sleep less than the recommended 7 hours per night. Additionally, ~20% of adults in the work force are shift- workers and therefore have elevated risk of circadian misalignment (i.e. sleeping during the biological day and wakefulness during the biological night). Health problems associated with insufficient sleep and circadian misalignment include inflammation, depression and anxiety, drug abuse, reduced insulin sensitivity, diabetes, and obesity. While the contribution of sleep to overall health is well recognized, many primary care providers fail to diagnose or recognize sleep and circadian disorders and estimates show undiagnosed sleep disorders are more prevalent than diagnosed sleep disorders. Currently, no clinical biomarkers of overall sleep and circadian health exist. Developing such biomarkers has the potential to: 1) improve diagnosis of sleep and circadian disorders; 2) identify biochemical mechanisms underlying increased risk of cardiometabolic disease associated with insufficient sleep and circadian misalignment; and 3) inform novel sleep and circadian based countermeasures. Long-term, biomarkers of sleep and circadian health could also support the development of personalized medicine, in part, by identifying individuals most likely to benefit from sleep and circadian based interventions. The overall goal of this K01 is to identify biomarkers of sleep loss and circadian misalignment, and assess the impact of increased sleep time on these biomarkers. I will use samples from two previously completed NIH- funded laboratory based protocols to identify putative biomarkers of insufficient sleep and circadian misalignment using plasma metabolomics and proteomics. I will also assess the plasma metabolome and insulin sensitivity in a four-week trial that increases nightly sleep duration to the recommended ≥7 hours sleep/night in habitual short-sleepers to determine if my identified biomarkers can discriminate these individuals between baseline insufficient sleep and post-increased sleep time and if increasing sleep time improves insulin sensitivity. This award will provide key training in four areas: 1) bioinformatics; 2) omics; 3) clinical translational sleep and circadian studies and interventions; and 4) professional development, and will provide essential preliminary data for an NIH R01 to help me launch an independent research program. The proposed outcomes support the 2011 NIH Sleep Disorders Research Plan to “enable sleep and circadian research training to inform science in cross-cutting domains, accelerate the pace of discovery, and the translation of enhanced therapies from bench to bedside to community”.