Urine metabolomics to estimate internal clock time

项目摘要 人体的内部时钟(即昼夜节律)控制着生理的许多方面的时间， 新陈代谢和行为。令人惊讶的是，大量的昼夜节律紊乱与此有关。 各种疾病，包括多种类型的抑郁症、自闭症、几种癌症和几种 神经退行性疾病，越来越多的证据表明，这些疾病的治疗是有时机的 最理想的是，就人体内部时钟而言，这对它们的有效性至关重要。主要有两种 然而，在临床实践中实施这种“基于昼夜节律”的干预措施存在障碍。首先，在时间上 健康人的体内生物钟可能会有5到8个小时的差异(患者群体中的变化更大)。 因此，尽管许多药物是基于一天中的时间给药的，例如早上给药与晚上给药，但一种药物 一个人在上午8点给药，另一个人可能在生物学上相当于凌晨3点的时间给药 个人的。其次，在非研究环境下，很难评估内部时钟时间。现行金本位 方法需要对表现出强健的昼夜节律的单个化合物进行连续测量(例如， 在24至48小时的采样窗口内)，这是侵入性的、耗时和昂贵的。 不是测量连续样品中的一种化合物，而是评估内部时钟时间的替代方法 是从一个样品中测量多个化合物。最近，几个组织报告说，他们有能力 根据从一到两个血液测量的多种代谢物或转录组节律来评估内部时钟时间 样本。虽然这些方法在估计体内生物钟时间的能力方面取得了重大进步，但血液 采样仍然是有侵入性的，从这些方法得出的内部时钟时间只有在 条件有限。在这里，我们提出了一个代谢组学方法来评估内部时钟时间从单个 尿液排空。我们最近对n=3名参与者进行的初步分析已经从超过 通过非靶向尿代谢组分析检测到4,000种注释代谢物。这股潮流的目标是 建议在更大的样本量中确认这些候选化合物，并测试这些 根据黄金标准衡量标准，准确评估内部时钟时间的化合物可达到30分钟以内。 以非侵入性和具有时间和成本效益的方式评估内部时钟时间的能力直接

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