Circadian Lipidomics in Constant Routine, Forced Desynchrony, and Non-lab Setting

 描述（由申请人提供）：昼夜节律定时中断已成为一个严重的健康和安全问题，但在不进行高度对照的多日住院研究的情况下，没有客观的方法可以轻松评估昼夜节律定时或调整。昼夜节律改变 定时可导致睡眠丧失和困倦、导致诸如机动车事故的表现错误以及损害记忆/学习。因此，尽管明显需要识别个体的昼夜节律相位/对齐，但我们不能在临床或回顾性研究中评估昼夜节律定时。毫不奇怪，2011年NIH睡眠障碍研究计划的第一个目标是确定：“......新陈代谢...睡眠不足的生物标志物和生物计时和昼夜节律紊乱，这将有助于个性化治疗，并澄清与未经治疗的睡眠和昼夜节律紊乱和干扰相关的风险。“我们意识到生物标志物开发面临的主要挑战，包括通常在多个时间点控制的代谢物变化的多因素原因。然而，由于昼夜节律时间与深刻的代谢、免疫和心血管变化相关，因此我们假设可以从单个血液样品中获得来自组学标记物的昼夜节律时相的生物标记物特征。因此，我们建议利用分析和生物信息学平台以及PI实验室在群体水平代谢组学研究方面的经验，在由四名合作研究者进行的六项严格控制的昼夜节律研究中，研究来自特征良好的个体的库存血浆样本。去识别，去优化，去验证，并交叉验证一组基于嵌套血浆脂质组学的生物标志物图谱，这些图谱报告了昼夜节律相位和使用良好的目的2：鉴定、优化、验证和交叉验证一组基于巢式血浆脂质组学的生物标志物谱，其使用从四种强制去脂方案中提取的充分表征的样品报告昼夜节律相位和排列。目的3：为了系统地评价来自目的1和2的经验证的谱及其数学相似性和差异，以便提高生物标志物的准确度和精密度目的4：为了在控制不良的真实的世界应用下测试以上鉴定的标志物。 生物标志物组的建立将影响科学和健康的多个方面：（i）有助于对昼夜节律紊乱的临床识别和治疗;（ii）通过个体化治疗时机来推进个体化医学以增强药物的功效/减少药物的副作用（例如，（iii）创建流行病学工具，将昼夜节律与疾病风险联系起来; 其他疾病生物标志物的发展，以及;（iv）有助于研究昼夜节律生物学及其对人类健康的影响。

 DESCRIPTION (provided by applicant): Disrupted circadian timing has emerged as a serious health and safety issue, yet there are no objective means of easily assessing circadian timing or alignment without performing a highly controlled, multiple-day in- patient study. Altered circadian timing can cause both sleep loss and sleepiness, cause performance errors such as motor vehicle accidents, and impair memory/learning. Thus, despite the obvious need to recognize an individual's circadian phase/alignment, we cannot assess circadian timing clinically or in retrospective studies. Not surprisingly, the first goal of the 2011 NIH Sleep Disorders Research Plan is to identify: "...metabolic... biomarkers of sleep deficiency and biological timing...and circadian disorders that will facilitate personalized treatments, and clarify the risk associated with untreated sleep and circadian disorders and disturbances." We are aware that major challenges face biomarker development, including multi-factorial causes of metabolite shifts normally controlled across multiple time-points. Because circadian time is associated with profound metabolic, immune and cardiovascular changes, however, we hypothesize that a biomarker signature for circadian phase derived from -omic markers can be obtained from a single blood sample. We therefore propose to utilize the analytical and bioinformatics platforms and experience in population-level metabolomics studies in the PIs lab to study banked plasma samples from the well-characterized individuals in six tightly controlled circadian rhythm studies run by the four co-investigators.The Aims are: Aim 1: To identify, to optimize, to validate, and t cross-validate a set of nested plasma lipidomics- based biomarker profiles that report circadian phase and alignment using well-characterized samples drawn from three constant routine protocols Aim 2: To identify, to optimize, to validate, and to cross-validate a set of nested plasma lipidomics based biomarker profiles that report circadian phase and alignment using well-characterized samples drawn from four forced desynchrony protocols Aim 3: To systematically evaluate the validated profiles from Aims 1 and 2 and their mathematical similarities and differences so as to improve accuracy and precision of the biomarkers Aim 4: To test the markers identified above under poorly controlled real world applications Identification of biomarker panels will impact multiple aspects of science and health: (i) contribute to clinical recognition and treatment on circadian disorders; (ii) advance personalized medicine through individualized treatment timing to enhance efficacy/reduce side effects of medications (e.g., chemotherapy); (iii) creating epidemiologic tools to relate circadian with disease risk; and aiding development of other disease biomarkers, and; (iv) contribute to research on circadian biology and its implications for human health.