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

恒定常规、强制不同步和非实验室环境中的昼夜脂质组学

• 批准号: 9083622
• 负责人: BRUCE S KRISTAL
• 金额: $ 84.9万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-18 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9083622
• 关键词: Address; Adverse effects; Age; Algorithms; Bioinformatics; Biological; Biological Clocks; Biological Markers; Biology; Birds; Blood specimen; Cardiovascular Diseases; Cardiovascular system; Chronic Disease; Circadian Rhythms; Clinic; Clinical; Computer Simulation; Data; Development; Diabetes Mellitus; Diagnosis; Diet; Disease; Environment; Epidemiology; Face; Gender; Generations; Goals; Health; Health Sciences; Hour; Human; Immune; Individual; Inpatients; Learning; Link; Machine Learning; Malignant Neoplasms; Mass Spectrum Analysis; Memory; Metabolic; Methods; Modeling; Patients; Pattern Recognition; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plasma; Population; Process; Protocols documentation; Reporting; Research; Research Personnel; Research Project Grants; Resolution; Resources; Retrospective Studies; Risk; Role; Running; Safety; Sampling; Sleep; Sleep Disorders; Smoking; Societies; Strigiformes; Testing; Time; United States National Institutes of Health; Work; base; biomarker development; biomarker panel; blood lipid; blood-based biomarker; chemotherapy; combinatorial; disorder risk; experience; human population study; improved; individualized medicine; meetings; men; metabolomics; older women; personalized medicine; public health relevance; public health research; real world application; tool; vehicular accident

 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.

 描述（由申请人提供）：昼夜节律紊乱已成为一个严重的健康和安全问题，但在不进行高度控制的、多天的住院患者昼夜节律改变研究的情况下，没有客观的方法可以轻松评估昼夜节律的定时或调整。 计时可能会导致睡眠不足和困倦，导致表现错误，例如机动车事故，并损害记忆/学习。因此，尽管明显需要识别个人的昼夜节律相位/对齐，但我们无法在临床或回顾性研究中评估昼夜节律计时。毫不奇怪，2011 年 NIH 睡眠障碍研究计划的第一个目标是确定：“……代谢……睡眠不足和生物计时的生物标志物……以及昼夜节律紊乱，这将有助于个性化治疗，并阐明风险与未经治疗的睡眠和昼夜节律紊乱和紊乱有关。”我们意识到生物标志物开发面临着重大挑战，包括通常在多个时间点控制的代谢变化的多因素原因。因为昼夜节律与深刻的代谢、免疫和心血管变化相关然而，我们追求从单组学标记中获得昼夜节律阶段的生物标记特征，因此我们建议利用分析和生物信息学平台以及人群水平代谢组学研究的经验。 PI 实验室将在由四位联合研究人员进行的六项严格控制的昼夜节律研究中研究来自特征明确的个体的储存血浆样本。目标是： 目标 1：识别、优化、验证和交叉验证一组基于嵌套血浆脂质组学的生物标志物概况，使用从三个恒定常规方案中抽取的良好表征的样本来报告昼夜节律阶段和对齐目标 2：识别、优化、验证和交叉验证一组基于嵌套血浆脂质组学的生物标志物概况，使用从四个强制去同步协议中抽取的充分表征的样本来报告昼夜节律阶段和对齐。 目标 3：系统地评估目标 1 和 2 中经过验证的概况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 目标 4：在控制不善的现实世界应用中测试上述识别的标志物 生物标志物组合将影响科学和健康的多个方面：(i) 有助于昼夜节律紊乱的临床识别和治疗；(ii) 通过个体化治疗时机推进个性化医疗，以提高药物疗效/减少药物副作用（例如化疗）； (iii) 创建流行病学工具将昼夜节律与疾病风险联系起来； 开发其他疾病生物标志物；(iv) 促进昼夜节律生物学及其对人类健康影响的研究。