Novel Circadian Biomarkers in Medical ICU Patients

项目总结 为了更好地了解和治疗危重疾病中睡眠和昼夜节律紊乱的病理生理学， 需要实用和准确的昼夜节律时间(即昼夜节律相位)的测量。睡眠动态平衡和 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 而在危重病人中，昼夜节律紊乱是公认的。目前对昼夜节律时间的测量是 资源密集型，需要在≥24小时内频繁(例如每小时)采集血液、唾液或尿液样本。因此，一把钥匙 在调查危重疾病、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多的患者，并纵向跟踪。最近， 开发了两个昼夜节律的转录生物标记物，并在正常受试者中进行了测试：时间签名 (次)和BodyTime(BodyT)。这些生物标志物准确地估计褪黑素的开始，只需要1到2个 每天的血样。TIMES和BodyT的准确性还没有在患有 高度的昼夜节律紊乱。这个项目的总体目标是测试新的昼夜节律的准确性 危重病人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 和BodyT，将准确地估计危重患者的褪黑素开始。我们测试这些的基本原理 生物标志物是其方便的抽血计划、低血容量需求和估计的准确性。 健康受试者褪黑素的发病时间。核心假设将通过以下具体情况进行检验 目的：目的1-建立褪黑素起效时间与尿液时间的准确性。 危重病患者在内科重症监护病房(MICU)时的aMT6s顶相变化 入院；和目标2-建立身体T在估计褪黑素相对于尿液起效时间方面的准确性 危重病患者在MICU入院时的AMT6s顶相。AIMS将在一个 MICU患者平行采集尿液和血液中的aMT6s(每小时)的观察队列 转录生物标志物分析(每6小时一次)，持续24小时。尿液aMT6s峰时相(即拟合峰时间 水平aMT6s)将作为昼夜时间参考。分析将包括测试总体准确性和 昼夜节律失调受试者之间的准确性比较。对于每个生物标记物，褪黑素的起始可以 使用4个可用样本中的2个进行估计；因此，每个生物标志物将具有多个样本对 分析。这些额外的样本对将用于比较基于样本计时相对于 每个受试者都有各自的昼夜节律。这项拟议的工作意义重大，因为确定了 这一具有挑战性的人群中的一种或两种生物标记物填补了目前减缓这一领域的显著空白，并且 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关键数据 危重病人的功能。

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.