Biomarkers and Altered Metabolic Pathways during Sleep Loss and Circadian Disruption

项目总结/摘要 大约有5000万至7000万美国人患有睡眠和觉醒障碍，超过35%的美国人 每晚睡眠少于建议的7小时。此外，劳动力中约20%的成年人是轮班工作者。 因此具有昼夜节律失调的升高的风险（即，在生物日期间睡觉， （生物学上的夜）。与睡眠不足和昼夜节律相关的健康问题 失调包括炎症、抑郁和焦虑、药物滥用、胰岛素敏感性降低、糖尿病 和肥胖。虽然睡眠对整体健康的贡献是公认的，但许多初级保健提供者未能 诊断或识别睡眠和昼夜节律紊乱，估计显示未诊断的睡眠障碍更多 比诊断的睡眠障碍更普遍。目前，没有整体睡眠和昼夜健康的临床生物标志物 存在.开发这样的生物标志物有可能：1）改善睡眠和昼夜节律紊乱的诊断; 2)确定与以下疾病相关的心脏代谢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）告知新的基于睡眠和昼夜节律的对策。 长期的，睡眠和昼夜健康的生物标志物也可以支持个性化治疗的发展。 医学，部分通过识别最有可能从睡眠和昼夜节律干预中受益的个体。 本K 01的总体目标是识别睡眠丧失和昼夜节律失调的生物标志物，并评估 增加睡眠时间对这些生物标志物的影响。我将使用两个先前完成的NIH样本- 资助的实验室为基础的协议，以确定假定的生物标志物的睡眠不足和昼夜节律 使用血浆代谢组学和蛋白质组学的不对准。我还会评估血浆代谢组和胰岛素 在一项为期四周的试验中， 习惯性短睡眠者，以确定我确定的生物标志物是否可以区分这些人 基线睡眠不足和后增加睡眠时间，以及增加睡眠时间是否改善胰岛素敏感性。 该奖项将提供四个领域的关键培训：1）生物信息学; 2）组学; 3）临床转化睡眠和 昼夜节律研究和干预措施; 4）专业发展，并将提供必要的初步 NIH R 01的数据来帮助我启动一个独立的研究项目。拟议成果支持 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，以告知科学， 交叉领域，加快发现的步伐，并将增强的疗法从实验室转化为 “社区的边缘”。

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”.