Urine metabolomics to estimate internal clock time

尿液代谢组学来估计内部时钟时间

• 批准号: 10024088
• 负责人: Melissa April St Hilaire
• 金额: $ 22.38万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-25 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10024088
• 关键词: Antihypertensive Agents; Award; Beds; Behavior; Biological; Biological Clocks; Blood specimen; Circadian Dysregulation; Circadian Rhythms; Clinic; Consumption; Diagnosis; Disease; Effectiveness; Ethnic group; Exhibits; Future; Goals; Gold; Hour; Individual; Inpatients; Intervention; Laboratory Study; Light; Mathematics; Measurement; Measures; Medicine; Melatonin; Mental Depression; Metabolism; Methods; Neurodegenerative Disorders; Participant; Patients; Perception; Periodicity; Pharmaceutical Preparations; Phase; Phototherapy; Physiology; Pilot Projects; Plasma; Posture; Reporting; Sample Size; Sampling; Schedule; Sleep; Testing; Therapeutic Intervention; Time; United States National Institutes of Health; Urine; Woman; Work; age group; autism spectrum disorder; awake; base; blind; cancer type; chemotherapy; circadian; clinical practice; cost; cost effective; improved; men; metabolomics; metabolomics resource; patient population; precision medicine; prospective; public health relevance; racial and ethnic; repository; shift work; standard measure; transcriptomics; urinary

Project Summary The body’s internal clock (i.e., circadian rhythm) controls the timing of many aspects of physiology, metabolism, and behavior. Disruption of circadian rhythms has been implicated in a surprisingly large number of diseases, including many types of depression, autism, several types of cancer, and several neurodegenerative disorders, and mounting evidence suggests that treatment for these diseases timed optimally with respect to the body’s internal clock is critical to their effectiveness. There are two primary barriers to implementing such “circadian-based” interventions in clinical practice, however. First, the timing of the internal clock can vary by 5 to 8 hours in healthy individuals (even more variable in patient populations). Thus, although many drugs are given based on time of day, e.g., morning vs. evening administration, a drug administered at 8am in one individual may be administered at the biologically equivalent time of 3am in another individual. Second, internal clock time is difficult to assess in a non-research setting. Current gold-standard methods require serial measurement of a single compound that exhibits a robust circadian rhythm (e.g., melatonin) over a 24- to 48-hour sampling window, which is invasive, time-consuming and costly. Instead of measuring one compound in serial samples, an alternate approach for assessing internal clock time is to measure multiple compounds from a single sample. Recently, several groups have reported the ability to assess internal clock time from multiple metabolite or transcriptomics rhythms measured from one or two blood samples. While these methods represent a major advance in the ability to estimate internal clock time, blood sampling remains invasive and the internal clock time derived from these methods is accurate only under limited conditions. Here, we propose a metabolomics approach to assess internal clock time from a single urine void. Our recent pilot analysis in n=3 participants has identified several candidate compounds from over 4,000 annotated metabolites detected by untargeted urine metabolomics profiling. The goal of this current proposal is to confirm these candidate compounds in a larger sample size and test the ability of these compounds to accurately assess internal clock time to within 30 minutes against a gold-standard measure. The ability to assess internal clock time in a non-invasive and time- and cost-effective manner has direct

项目摘要 人体的内部时钟（即，昼夜节律）控制生理学的许多方面的定时， 新陈代谢和行为。生物钟节律的紊乱已经被牵连在一个令人惊讶的数量 疾病，包括许多类型的抑郁症，自闭症，几种类型的癌症， 神经退行性疾病，越来越多的证据表明，治疗这些疾病的时间， 最佳地相对于身体的内部时钟是至关重要的他们的有效性。有两个主要 然而，在临床实践中实施这种“基于昼夜节律”的干预措施的障碍。首先， 在健康个体中，内部时钟可以变化5至8小时（在患者群体中甚至更可变）。 因此，尽管许多药物是基于一天中的时间给予的，例如，早晨与晚上给药，药物 在一个个体中在上午8点给药可以在另一个个体中在上午3点的生物等效时间给药 单独的.其次，在非研究环境中，内部时钟时间很难评估。现行金本位制 这些方法需要连续测量表现出强健的昼夜节律的单一化合物（例如， 褪黑激素）在24至48小时的采样窗口内进行，这是侵入性的、耗时且成本高昂。 代替测量连续样品中的一种化合物， 是从一个样本中测量多种化合物。最近，几个小组报告说， 从一个或两个血液测量的多种代谢物或转录组学节律评估内部时钟时间 样品虽然这些方法代表了估计内部时钟时间能力的重大进步，但血液 采样仍然是侵入性的，从这些方法中得出的内部时钟时间只有在以下情况下才是准确的 有限的条件。在这里，我们提出了一种代谢组学的方法来评估内部时钟时间从一个单一的 排尿。我们最近在n=3名参与者中进行的初步分析已经从超过100种化合物中鉴定出了几种候选化合物。 通过非靶向尿液代谢组学分析检测到4，000种注释代谢物。这股潮流的目标 建议是在更大的样本量中确认这些候选化合物，并测试这些化合物的能力。 化合物，以准确地评估内部时钟时间，在30分钟内对黄金标准措施。 以非侵入性和时间和成本效益的方式评估内部时钟时间的能力具有直接的