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 该项目的目标是通过开发健壮的 用于昼夜节律计时的诊断生物标记物，以从单个生物样本中识别生物时间 一个个体。我们对昼夜节律对人类健康重要性的认识正在增加； 昼夜节律紊乱与代谢紊乱、心血管疾病、免疫 调节失调和癌症。最近的一项研究测试了大约17,000个基因，发现近一半的基因在 至少一个人体组织，其中900多个循环基因编码的蛋白质是药物 靶向，运输药物，或参与药物代谢。在这种新兴知识的基础上，我们 应该能够规律化昼夜节律以预防疾病，并管理许多短暂的半衰期 在理想的昼夜时间服用药物，以提高疗效和/或减少副作用。然而，我们有能力 将昼夜节律计时纳入临床决策和治疗因我们目前的无能而受到损害 为了快速、方便地测量昼夜节律。 目前评估昼夜节律的方法需要几个小时(甚至一天)的采样，而 病人的情况已得到控制。在父母的资助中，我们的目标是开发出能够估计 单独的昼夜节律时间，在白天或晚上的任何时间使用血浆采集单一血液样本 基于蛋白质组学的方法来识别一组节奏蛋白质，以及提炼基于单核细胞的 方法使用15份成绩单组成的小组。在这个新的研究方向项目中，我们将扩大我们的 昼夜节律生物标记物努力包括开发用于昼夜节律的呼吸生物标记物。 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 光谱(SIFT-MS)以搜索昼夜时间的呼吸生物标志物。我们将添加以下集合 使用严格的恒定程序，每3小时对父母资助的研究进行一次呼吸采样 在高度受控的实验室条件下确保任何观察到的呼吸振荡的方法学 代谢物是由于呼吸成分的内源性变化，而不是代表反应 与活动、食物/液体摄入量或成分或睡眠-觉醒状态的变化有关。我们会确认呼吸是否有效 代谢组学生物标志物与来自血浆褪黑激素的昼夜节律阶段估计(当前 “金标”相标)。当完全开发时，这种基于呼吸的方法将实现按需 对昼夜节律状态的非侵入性实时监测。提出了新的研究方向 该项目有可能开发一种快速、实时、非侵入性的诊断和治疗方法 怀疑有昼夜节律紊乱的患者(延迟睡眠-觉醒相紊乱、倒班工作 睡眠障碍)和其他睡眠病理(失眠、嗜睡)，并促进潜在的 通过个体化治疗时机实现个体化用药(时间医学)。 -1-