Proteomic and Transcriptomic Biomarkers of Circadian Timing

昼夜节律的蛋白质组和转录组生物标志物

• 批准号: 10461968
• 负责人: Jeanne F Duffy
• 金额: $ 83.36万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10461968
• 关键词: Acute; Adult; Affect; Behavior; Biological; Biological Assay; Biological Markers; Blood specimen; Brain; Cardiovascular Diseases; Circadian Dysregulation; Circadian Rhythm Disorder; Circadian Rhythm Sleep Disorders; Circadian Rhythms; Code; Consumption; Data; Data Collection; Diagnosis; Disadvantaged; Disease; Drug Targeting; Drug Transport; Ensure; Genes; Goals; Gold; Half-Life; Health; Hour; Human; Hypersomnias; Immune; Impairment; Individual; Knowledge; Laboratories; Light; Malignant Neoplasms; Measurement; Measures; Melatonin; Metabolic Diseases; Metabolism; Methods; Participant; Pathology; Pathway interactions; Patients; Pattern; Performance; Periodicity; Peripheral; Pharmaceutical Preparations; Phase; Physiological; Physiology; Plasma; Plasma Proteins; Posture; Procedures; Process; Proteins; Proteomics; Rest; Safety; Saliva; Salivary; Sampling; Schedule; Series; Shift-Work Sleep Disorder; Sleep; Sleep Deprivation; Sleep disturbances; Sleeplessness; Techniques; Testing; Time; Tissues; Transcript; Travel; Whole Blood; base; biomarker panel; circadian; circadian pacemaker; clinical decision-making; diagnostic biomarker; human tissue; improved; individualized medicine; monocyte; nano-string; novel; personalized medicine; prevent; protein biomarkers; side effect; transcriptomics

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 metabolism1. 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. We aim to develop a method that can estimate individual circadian time with a single blood sample taken at any time of the day or night. To do this, we will use two state of the art methods, a plasma proteomics-based method to identify a panel of rhythmic proteins (extending our preliminary data) and a whole blood-derived monocyte-based method using a panel of 15 transcripts (to validate and extend a recent study). We will ensure the selected protein biomarker panel is robust to varying sleep-wake patterns by collecting samples under conditions of habitual sleep timing, under shortened “weekday” sleep and extended “weekend” sleep, and across ~40 hours of controlled posture, wake, and behaviour from a group of healthy, entrained, well- rested adults studied for a week in highly controlled laboratory conditions. We will also test both methods in a series of patients with circadian rhythm sleep disorders. We will validate separately the proteomics-based biomarker and the monocyte-based transcript biomarker, and also explore whether combining them can improve the accuracy of our timing estimates. In all cases, circadian phase estimates from the biomarker panels will be compared with those derived from plasma or saliva melatonin (the current “gold-standard” circadian phase marker). The proposed project has the potential to: 1) reveal novel physiological pathways affected by circadian timing and sleep; 2) pave the way for improved diagnosis and treatment for patients with suspected circadian rhythm disorders (delayed sleep-wake phase disorder, shift work disorder) and other sleep pathologies (insomnia, hypersomnia); 3) advance personalized medicine through individualized treatment timing (chronomedicine).

抽象的 该项目的目标是通过开发强大的诊断技术来优化人类健康、表现和安全 用于昼夜节律计时的生物标记物，用于从单个生物样本中识别个体内的生物时间。 我们越来越了解昼夜节律对人类健康的重要性；昼夜节律紊乱 时机与代谢紊乱、心血管疾病、免疫失调和癌症有关。一个 最近的研究测试了约 17,000 个基因，发现近一半的基因在至少一个人体组织中循环，并且超过 其中 900 个循环基因编码的蛋白质是药物靶标、转运药物或参与药物 新陈代谢1.基于这些新兴知识，我们应该能够规范昼夜节律，以预防 疾病，并在理想的昼夜节律时间施用许多短半衰期药物以提高疗效和/或 减少副作用。然而，我们将昼夜节律纳入临床决策的能力和 由于我们目前无法快速、轻松地测量昼夜节律相位，治疗受到损害。 目前评估昼夜节律的方法需要在数小时（甚至长达一天）内进行采样，而 患者处于受控状态。我们的目标是开发一种可以估计个人昼夜节律时间的方法 在白天或晚上的任何时间采集的单一血液样本。为此，我们将使用两种最先进的方法， 基于血浆蛋白质组学的方法来识别一组节律蛋白（扩展我们的初步数据）和 一种基于全血的单核细胞方法，使用一组 15 个转录本（以验证和扩展最近的 学习）。我们将通过收集来确保所选的蛋白质生物标志物组对不同的睡眠-觉醒模式具有稳健性 习惯性睡眠时间、缩短“工作日”睡眠和延长“周末”睡眠条件下的样本 睡眠，以及一组健康、训练有素、状态良好的人在约 40 小时内控制姿势、清醒和行为。 休息的成年人在高度控制的实验室条件下研究了一周。我们还将在 一系列昼夜节律睡眠障碍患者。我们将分别验证基于蛋白质组学的 生物标志物和基于单核细胞的转录物生物标志物，并探索将它们结合起来是否可以改善 我们的时间估计的准确性。在所有情况下，生物标记物组的昼夜节律阶段估计值将是 与来自血浆或唾液褪黑激素（当前“黄金标准”昼夜节律阶段）的褪黑激素相比 标记）。 拟议的项目有潜力：1）揭示受昼夜节律影响的新生理途径 和睡觉； 2）为改善疑似昼夜节律患者的诊断和治疗铺平道路 障碍（睡眠-觉醒时相延迟障碍、轮班工作障碍）和其他睡眠病症（失眠、 嗜睡）； 3）通过个体化治疗时机（时间医学）推进个体化医疗。