Proteomic and Transcriptomic Biomarkers of Circadian Timing

摘要 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，性能和安全性。 生物标志物用于昼夜节律计时，以从单个生物样本识别个体内的生物时间。 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 定时与代谢紊乱、心血管疾病、免疫失调和癌症有关。一 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至少一个人体组织中循环，超过一半的基因在人体组织中循环。 其中900个循环基因编码的蛋白质是药物靶点，转运药物或参与药物代谢。 新陈代谢1.基于这一新兴知识，我们应该能够调整昼夜节律， 药物治疗，并在其理想的昼夜节律时间施用许多短半衰期药物以增加功效和/或 减少副作用。然而，我们将昼夜节律纳入临床决策的能力， 治疗由于我们目前不能快速和容易地测量昼夜节律相位而受到损害。 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，而 患者处于受控状态。我们的目标是开发一种方法，可以估计个人的昼夜节律时间， 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， 一种基于血浆蛋白质组学的方法来鉴定一组节律蛋白（扩展了我们的初步数据）， 一种基于全血衍生单核细胞的方法，使用一组15个转录本（以验证和扩展最近的 研究）。我们将确保所选的蛋白质生物标志物面板对不同的睡眠-觉醒模式具有鲁棒性， 在习惯性睡眠时间、缩短“工作日”睡眠和延长“周末”睡眠条件下的样本 睡眠，并在约40小时的控制姿势，唤醒，和行为，从一组健康，夹带，良好， 在高度受控的实验室条件下对休息的成年人进行了为期一周的研究。我们还将在一个 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，并探讨是否将它们结合起来可以改善 我们时间估计的准确性在所有情况下，来自生物标志物组的昼夜节律相位估计将是 与来自血浆或唾液褪黑激素（目前的“黄金标准”昼夜节律相位）的那些相比， 标记）。 该项目有可能：1）揭示受昼夜节律影响的新生理途径 和睡眠; 2）为改善疑似昼夜节律患者的诊断和治疗铺平道路 障碍（延迟睡眠-觉醒期障碍，轮班工作障碍）和其它睡眠病理（失眠， 睡眠过度）; 3）通过个体化治疗时机（时间医学）推进个体化医学。

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).