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

 描述(申请人提供)：昼夜节律紊乱已经成为一个严重的健康和安全问题，但在没有进行高度受控的多天住院研究的情况下，没有客观的方法来轻松评估昼夜节律或对齐。昼夜节律改变 计时可能会导致失眠和困倦，导致机动车事故等性能错误，并损害记忆/学习。因此，尽管明显需要识别个体的昼夜节律，但我们不能在临床上或在回顾性研究中评估昼夜节律。不足为奇的是，2011年美国国立卫生研究院睡眠障碍研究计划的第一个目标是确定：“……新陈代谢……睡眠不足和生物计时的生物标志物……以及有助于个性化治疗的昼夜节律紊乱，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。”我们意识到生物标记物开发面临的主要挑战，包括通常跨多个时间点控制的代谢物转移的多因素原因。然而，由于昼夜节律时间与深刻的代谢、免疫和心血管变化有关，我们假设从单个血液样本中可以获得来自基因组标志物的昼夜节律阶段的生物标志物特征。因此，我们建议利用PIS实验室在人群水平代谢组学研究中的分析和生物信息学平台和经验，在由四个合作调查员运行的六个严格控制的昼夜节律研究中研究来自特征良好的个体的银行血浆样本。目标1：识别、优化、验证和t交叉验证一组基于嵌套血浆脂质组学的生物标记物轮廓，其使用来自三个恒定常规方案的良好特征的样本来报告昼夜节律和排列。目标2：识别、优化、验证、和交叉验证以及交叉验证一组基于嵌套血浆脂质组学的生物标记物轮廓，其使用来自四个强制去同步协议的特征良好的样本来报告昼夜节律和排列目标3：系统地评估来自目标1和2的验证轮廓以及它们的数学异同，以提高生物标记物的准确度和精密度目标4：在控制不佳的真实世界应用识别下测试上述识别的标记 生物标志物小组的发展将对科学和健康的多个方面产生影响：(1)有助于临床认识和治疗昼夜节律紊乱；(2)通过个体化的治疗时机推进个性化药物治疗，以提高疗效/减少药物(如化疗)的副作用；(3)创造流行病学工具，将昼夜节律与疾病风险联系起来；以及 开发其他疾病生物标志物；(4)促进昼夜节律生物学及其对人类健康的影响的研究。

 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.