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-

抽象的 该项目的目的是通过发展强大的 昼夜节律时间安排的诊断生物标志物，从单个生物测量中识别出生物学时间 一个人。我们对昼夜节律对人类健康的重要性的理解正在增加。 昼夜节律的破坏与代谢疾病，心血管疾病，免疫疾病有关 失调和癌症。最近的一项研究测试了约17,000个基因，发现几乎一半循环 至少一个人体组织，其中900多个循环基因编码为药物的蛋白质 靶标，运输药物或参与药物代谢。在这些新兴知识的基础上，我们 应该能够使昼夜节律定时以防止疾病，并管理许多短期的半衰期 在理想的昼夜节律时期的药物提高效率和/或降低副作用。但是，我们的能力 我们当前的无能为力地将昼夜节律的时间纳入临床决策和治疗会受到损害 快速轻松地测量昼夜节律。 当前评估昼夜节律时间的方法需要在数小时（甚至一天）中进行采样 患者处于受控状态。在父母赠款中，我们旨在开发可以估计的方法 单个昼夜节时间，白天或晚上的任何血液样本使用等离子体 基于蛋白质组学的方法来识别一组节奏蛋白，并精炼基于单核细胞 方法使用15个成绩单的面板。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，包括开发用于昼夜节律时机的呼吸生物标志物。 我们将使用称为“入选离子流量管质量”的实时呼气代谢组学技术 光谱法（SIFT-MS）搜索昼夜节律的呼吸生物标志物。我们将添加集合 使用严格的常规例行程序，每3小时呼吸一次对父母赠款的研究 在高度控制的实验室条件下的方法，以确保呼吸中的任何观察到的振荡 代谢物是由于呼吸成分的内源性变化而不是表示反应 改变活动，食物/液体摄入或组成或睡眠效果状态。我们将验证呼吸 代谢组学生物标志物针对来自血浆褪黑激素的昼夜节相估计值（电流 “金标准”相标）。当完全开发时，这种基于呼吸的方法将实现按需 无创和实时监测昼夜节律状态。拟议的新研究方向 项目有可能开发快速，实时，无创的诊断和治疗方法 怀疑昼夜节律疾病的患者（睡眠效果延迟，转移工作 障碍）和其他睡眠病理学（失眠，大肠症），并提高潜力 通过个性化治疗时机（钟表霉）个性化医学。 -1-