Real-time breath metabolomics: A new direction for circadian biomarkers

实时呼吸代谢组学：昼夜节律生物标志物的新方向

• 批准号: 10526014
• 负责人: Charles A Czeisler
• 金额: $ 17.9万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10526014
• 关键词: Address; Adult; Air; Alcohols; Behavior; Biological; Biological Markers; Biological Process; Blood; Blood specimen; Calibration; Cardiovascular Diseases; Circadian Dysregulation; Circadian Rhythm Disorder; Circadian Rhythms; Clinical Research; Code; Collection; Consumption; Data; Data Collection; Detection; Development; Devices; Diagnosis; Disadvantaged; Disease; Dose; Drug Targeting; Drug Transport; Ensure; Exhalation; Food; Genes; Goals; Gold; Half-Life; Health; Hour; Human; Human Biology; Hypersomnias; Immune; Impairment; Individual; Intake; Ions; Kinetics; Knowledge; Laboratories; Light; Liquid substance; Malignant Neoplasms; Mass Spectrum Analysis; Measurement; Measures; Melatonin; Metabolic Diseases; Metabolism; Methodology; Methods; Monitor; National Heart, Lung, and Blood Institute; Outcome; Pathology; Patients; Pattern; Performance; Periodicity; Peripheral; Pharmaceutical Preparations; Phase; Physiology; Plasma; Plasma Proteins; Posture; Preparation; Procedures; Proteins; Proteomics; Reaction; Reagent; Research; Research Personnel; Resources; Safety; Sampling; Schedule; Shift-Work Sleep Disorder; Sleep; Sleep Disorders; Sleep disturbances; Sleeplessness; Strategic vision; Technology; Testing; Time; Tissues; Transcript; Translations; Travel; Tube; United States National Aeronautics and Space Administration; Variant; base; biomarker panel; circadian; circadian pacemaker; clinical care; clinical decision-making; detection limit; diagnostic biomarker; drug metabolism; epidemiology study; experimental study; human disease; human tissue; individualized medicine; instrument; mass spectrometer; metabolomics; monocyte; parent grant; patient population; personalized medicine; point of care; prevent; rapid technique; response; sample collection; side effect

ABSTRACT The goal of the project is to optimize human health, performance, and safety by developing robust diagnostic biomarkers for circadian timing to identify, from a single biospecimen, the biological time within an individual. Our understanding of the importance of circadian timing to human health is increasing; disruption of circadian timing is associated with metabolic disorders, cardiovascular disease, immune dysregulation, and cancers. A recent study tested ~17,000 genes and found that nearly half cycled in at least one human tissue, and more than 900 of those cycling genes coded for proteins that are drug targets, transport drugs, or are involved in drug metabolism. Building on this emerging knowledge, we should be able to regularize circadian timing to prevent disease, and to administer many short half-life drugs at their ideal circadian time to increase efficacy and/or reduce side effects. However, our ability to incorporate circadian timing into clinical decision-making and treatment is impaired by our current inability to measure circadian phase quickly and easily. Current methods for assessing circadian timing require sampling over hours (or even up to a day) while the patient is in controlled conditions. In the parent grant we aim to develop methods that can estimate individual circadian time with a single blood sample taken at any time of the day or night using a plasma proteomics-based method to identify a panel of rhythmic proteins, as well as refining a monocyte-based method using a panel of 15 transcripts. In this New Research Direction project, we will expand our circadian biomarker efforts to include development of a breath biomarker for circadian timing. We will use real-time breath metabolomics technology called selected-ion flow-tube mass spectrometry (SIFT-MS) to search for breath biomarkers of circadian time. We will add collection of breath samples every 3 hours to the studies in the parent grant, using the rigorous constant routine methodology in highly controlled laboratory conditions to ensure any observed oscillations in breath metabolites are due to endogenous variations in breath components rather than representing responses to changes in activity, food/fluid intake or composition, or sleep-wake state. We will validate the breath metabolomics biomarker against circadian phase estimate derived from plasma melatonin (the current “gold-standard” phase marker). When fully developed, this breath-based method will enable on-demand monitoring of circadian status non-invasively and in real-time. The proposed New Research Direction project has the potential to develop a rapid, real-time, non-invasive method for diagnosis and treatment of patients with suspected circadian rhythm disorders (delayed sleep-wake phase disorder, shift work disorder) and other sleep pathologies (insomnia, hypersomnia) and to advance the potential of personalized medicine through individualized treatment timing (chronomedicine). -1-

摘要 该项目的目标是优化人类健康，性能和安全，通过开发强大的 用于昼夜节律计时的诊断生物标志物，以从单个生物样本中识别生物时间， 单个.我们对昼夜节律对人类健康的重要性的理解正在增加; 昼夜节律的紊乱与代谢紊乱、心血管疾病、免疫系统疾病、 失调和癌症。最近的一项研究测试了约17，000个基因，发现近一半的基因在2000年左右循环。 至少一个人体组织，以及900多个编码蛋白质的循环基因， 靶向、转运药物或参与药物代谢。基于这一新兴知识，我们 应该能够调节昼夜节律以预防疾病，并施用许多短半衰期的药物， 药物在其理想的昼夜节律时间，以增加功效和/或减少副作用。然而，我们的能力， 将昼夜节律定时纳入临床决策和治疗受到我们目前无法 快速轻松地测量昼夜节律。 目前用于评估昼夜节律定时的方法需要在数小时（或甚至长达一天）内采样， 病人的情况得到控制。在父母补助金中，我们的目标是开发可以估计 在白天或晚上的任何时间使用血浆采集单个血液样本， 一种基于蛋白质组学的方法来识别一组节律蛋白，以及改进基于单核细胞的 方法使用一组15个转录本。在这个新的研究方向项目中，我们将扩大我们的 昼夜节律生物标志物的努力包括用于昼夜节律计时的呼吸生物标志物的开发。 我们将使用实时呼吸代谢组学技术称为选择离子流管质量 使用SIFT-MS来搜索昼夜节律时间的呼吸生物标志物。我们将添加收集 呼吸样本，每3小时的研究在父母补助金，使用严格的恒定例程 在高度受控的实验室条件下，确保任何观察到的呼吸振荡 代谢物是由于呼吸成分的内源性变化，而不是代表响应 活动、食物/液体摄入或成分或睡眠-觉醒状态的变化。我们将确认呼吸 针对源自血浆褪黑激素的昼夜节律相位估计的代谢组学生物标志物（目前的 “黄金标准”相位标记）。当完全开发时，这种基于呼吸的方法将使按需 非侵入性和实时监测昼夜节律状态。拟议的新研究方向 该项目有潜力开发一种快速，实时，非侵入性的诊断和治疗方法 疑似昼夜节律紊乱的患者（睡眠-觉醒相紊乱延迟、轮班工作 障碍）和其他睡眠病理（失眠，嗜睡），并提高潜力， 通过个体化治疗时机（时间医学）的个性化医疗。 -1-