Delirium, Acute Inflammation, and Rhythmic Transcriptomics (DART)

谵妄、急性炎症和节律转录组学 (DART)

• 批准号: 10727587
• 负责人: Sarah Kendall Smith
• 金额: $ 31.1万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727587
• 关键词: Acute; Age; Analysis of Variance; Attention; Biological Markers; Blood specimen; Bypass; Cardiac Surgery procedures; Central Nervous System; Circadian Dysregulation; Circadian Rhythms; Clinical Data; Clinical Research; Cognition; Conscious; Critical Care; Critical Illness; Data; Data Set; Delirium; Development Plans; Dimensions; Elderly; Evaluation; Exhibits; Family member; Functional disorder; Funding; Future; Gene Expression Profiling; General Anesthesia; Genes; Hospitalization; Hospitals; Hour; Impairment; Incidence; Individual; Inflammation; Inflammatory Response; Injury; Interleukin-6; Interleukin-8; Leadership; Light; Link; Measurement; Measures; Mediating; Methods; Molecular; Morbidity - disease rate; Multiomic Data; Neurobiology; Neurology; Operative Surgical Procedures; Patients; Pattern; Periodicity; Perioperative; Physiological; Physiological Processes; Postoperative Period; Principal Component Analysis; Proteins; Proteomics; Research; Risk; Secure; Severities; System; TNF gene; Time; Tissue-Specific Gene Expression; United States; Whole Blood; body system; circadian; circadian pacemaker; clinically relevant; cohort; confusion assessment method; cost; data reduction; design; hospital care; innovation; machine learning algorithm; mortality; nervous system disorder; neurofilament; novel; patient stratification; postoperative delirium; predictive marker; programs; prospective; protein biomarkers; protein expression; systemic inflammatory response; theories; transcriptome sequencing; transcriptomics

PROJECT SUMMARY Postoperative delirium in older adults imposes massive burdens on patients, family members, and hospital systems with United States costs upwards of $32 billion. Despite this, the pathophysiology of postoperative delirium remains poorly understood and no therapies exist. Disruption of the circadian clock system is a putative contributor to postoperative delirium. The circadian clock system coordinates the timing of most physiologic processes including the systemic inflammatory response, whose dysfunction has been linked to postoperative delirium incidence and severity. It is unknown whether acute, perioperative disruption of the circadian clock system leads to an aberrant systemic inflammatory response to precipitate postoperative delirium. Elucidation of these dynamic, bidirectional relationships may yield novel predictive biomarkers and therapies to reduce delirium risk. We have recently validated a machine-learning algorithm, TimeSignature (TS), that uses transcriptomic data from whole blood to measure internal circadian transcriptomic time in a cohort of older adults. TS can be used to determine the transcriptomic angle, or the magnitude of discrepancy between internal transcriptomic time and true time of blood sampling in an individual. In this proposal, we aim to determine temporal links between changes in transcriptomic angle, systemic inflammation, and delirium severity in a cohort of older adults undergoing elective cardiac surgery. The central hypothesis is that patients stratified by delirium severity will exhibit distinct longitudinal molecular patterns of circadian rhythms and systemic inflammation perioperatively. In Aim 1, we will determine whether patients stratified by delirium severity exhibit distinct longitudinal patterns of transcriptomic angle across the perioperative continuum. Older adults stratified by delirium severity will undergo serial measurement of transcriptomic angle at three perioperative timepoints: on the day before cardiac surgery, on postoperative day (POD) 1, and POD 4. In Aim 2, we will evaluate whether incorporating proteomic biomarker data enhances distinguishing longitudinal patterns among delirium severity groups. The same patients from Aim 1 will undergo serial measurement of a comprehensive panel of protein biomarkers related to acute inflammation and neurobiological injury. The contribution of this proposal is significant because it represents critical first step in establishing the clinical relevance of molecular circadian rhythm disruptions during the perioperative period. The proposed research is innovative because it will shift current delirium research paradigms towards a precision-based approach ideally suited for hospitalized and critically-ill older adults undergoing major surgery.

项目摘要 老年人术后谵妄给患者、家属和医院带来了巨大的负担 系统 美国的成本超过 320亿美元尽管如此，术后的病理生理学 谵妄仍然知之甚少，没有治疗方法。 生物钟系统的破坏是术后谵妄的一个假定因素。生物钟 系统协调包括全身炎症反应在内的大多数生理过程的时间， 其功能障碍与术后谵妄的发生率和严重程度有关。目前尚不清楚是否急性， 围手术期生物钟系统的破坏导致异常的全身炎症反应， 导致术后谵妄阐明这些动态、双向的关系可能会产生新颖的成果 预测性生物标志物和治疗以降低谵妄风险。 我们最近验证了一种使用转录组数据的机器学习算法TimeSignature（TS） 以测量老年人队列中的内部昼夜节律转录组时间。TS可用于 以确定转录组角度，或内部转录组时间 和个体血液采样的真实时间。在本提案中，我们的目标是确定 一组老年人转录组角度、全身炎症和谵妄严重程度的变化 接受择期心脏手术中心假设是，根据谵妄严重程度分层的患者将 表现出不同的昼夜节律和围手术期全身炎症的纵向分子模式。 在目标1中，我们将确定根据谵妄严重程度分层的患者是否表现出不同的纵向模式， 转录组学角度在围手术期连续体。根据谵妄严重程度分层的老年人将接受 在三个围手术期时间点连续测量转录组角度：在心脏手术前一天， 术后第1天和第4天。在目标2中，我们将评估是否纳入蛋白质组生物标志物 数据增强了区分谵妄严重程度组之间的纵向模式。同样是Aim的病人 1名患者将接受一系列与急性炎症相关的蛋白质生物标志物的全面测量 和神经生物学损伤。这项建议的贡献是重大的，因为它是关键的第一步 在建立围手术期分子昼夜节律紊乱的临床相关性。 拟议的研究是创新的，因为它将改变目前的谵妄研究范式， 基于精确度的方法，非常适合住院和重症老年人接受大手术。