Novel Circadian Biomarkers in Medical ICU Patients

项目摘要 为了更好地理解和治疗危重病中睡眠和昼夜节律紊乱的病理生理学， 昼夜节律时间的实际和准确的测量（即，生理周期）。睡眠稳态和 昼夜节律是基本的、相互依赖的生理过程。严重睡眠的高患病率 重症患者的昼夜节律紊乱已得到证实。目前的昼夜节律时间的测量方法是 资源密集型，需要频繁的（例如，血液、唾液或尿液采样≥24小时。因此，一把钥匙 在调查危重病睡眠和昼夜节律紊乱方面的差距是缺乏实际和准确的措施 昼夜节律时间，可以有效地应用于更大数量的患者和纵向跟踪。最近， 在正常受试者中开发并测试了两种昼夜节律时间的转录生物标志物： （TimeS）和BodyTime（BodyT）。这些生物标志物准确估计褪黑激素起效， 每天采集血样。TimeS和BodyT的准确性尚未在患有以下疾病的危重受试者中进行测试： 高度的昼夜节律紊乱该项目的总体目标是测试新的昼夜节律的准确性 在危重患者队列中的生物标志物。中心假设是这些新的昼夜节律生物标志物，时间S 和BodyT，将准确估计重症患者的褪黑激素起效。我们测试这些的基本原理 生物标志物的优点是其方便的抽血时间表、低血容量要求和估计的准确性， 在健康受试者中褪黑激素起效的时间。中心假设将通过以下具体方法进行检验 目的：目的1 -确定TimeS在估计褪黑激素相对于尿6-HT起效时间方面的准确性。 重症监护室（MICU）重症患者的硫酸氧褪黑激素（aMT 6s）峰值时相 目的2 -确定BodyT在估计褪黑激素相对于尿液的起效时间方面的准确性 危重患者在MICU入院时的aMT 6s峰期。这些目标将在一个 MICU患者的观察性队列，这些患者接受尿液aMT 6s（每小时）和血液的平行采样， 转录生物标志物分析（每6小时）24小时。尿aMT 6s顶相（即，拟合峰时间 水平aMT 6s）将是昼夜节律时间参考。分析将包括总体准确性测试和 昼夜节律失调受试者之间的准确性比较。对于每一种生物标志物，褪黑激素的发作可以 使用4个可用样品中的2个进行估计;因此，每个生物标志物将具有用于 分析.这些额外的样本对将用于比较基于样本定时的准确度， 每个人的生理节奏时间建议的工作是重要的，因为建立的准确性， 这一具有挑战性的群体中的任一种或两种生物标志物填补了目前减缓该领域的显著空白， 为下一项旨在通过促进睡眠和昼夜节律改善结果的研究提供了关键数据。 在重症患者中发挥作用。

PROJECT SUMMARY To better understand and treat the pathophysiology of sleep and circadian disruption in critical illness, practical and accurate measures of circadian time (i.e., circadian phase) are needed. Sleep homeostasis and circadian rhythms are fundamental, interdependent physiologic processes. The high prevalence of severe sleep and circadian disruption is well established in critically ill patients. Current measures of circadian time are resource intensive, requiring frequent (e.g., hourly) sampling of blood, saliva, or urine for ≥24 hours. Thus, a key gap in investigating critical illness sleep and circadian disruption is the lack of practical and accurate measures of circadian time that can be applied efficiently to larger numbers of patients and followed longitudinally. Recently, two transcriptional biomarkers of circadian time were developed and tested in normal subjects: TimeSignature (TimeS) and BodyTime (BodyT). These biomarkers accurately estimate melatonin onset and require only 1 or 2 blood samples per day. The accuracy of TimeS and BodyT has not been tested in critically ill subjects who have a high degree of circadian disruption. This project’s overall objective is to test the accuracy of novel circadian biomarkers in a critically ill patient cohort. The central hypothesis is that these novel circadian biomarkers, TimeS and BodyT, will accurately estimate melatonin onset in critically ill patients. Our rationale for testing these biomarkers is their convenient blood draw schedule, low blood volume requirements, and accuracy in estimating time of melatonin onset among healthy subjects. The central hypothesis will be tested via the following specific aims: Aim 1 - Establish the accuracy of TimeS in estimating time of melatonin onset relative to urine 6- sulfatoxymelatonin (aMT6s) acrophase in critically ill patients at the time of medical intensive care unit (MICU) admission; and Aim 2 - Establish the accuracy of BodyT in estimating time of melatonin onset relative to urine aMT6s acrophase in critically ill patients at the time of MICU admission. The aims will be tested in an observational cohort of MICU patients who undergo parallel sampling of urine aMT6s (hourly) and blood for transcriptional biomarker analysis (every 6 hours) for 24 hours. Urine aMT6s acrophase (i.e., time of fitted peak level aMT6s) will be the circadian time reference. Analysis will include tests for overall accuracy and a comparison of accuracy among subjects with circadian misalignment. For each biomarker, melatonin onset can be estimated using 2 of the 4 available samples; thus, each biomarker will have multiple sample pairs for analysis. These additional sample pairs will be used to compare accuracy based on sample timing relative to each subject’s individual circadian time. The proposed work is significant because establishing the accuracy of either or both biomarkers in this challenging population fills a significant gap that currently slows the field and provides key data for the next investigation aimed at improving outcomes by promoting sleep and circadian function in critically ill patients.