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 老年人的术后del妄对患者，家庭成员和医院施加巨大负担 系统 美国成本高达 320亿美元。尽管如此，术后的病理生理学 ir妄仍然知之甚少，没有疗法。 昼夜节律系统的破坏是术后del妄的推定贡献者。昼夜节律 系统协调大多数生理过程的时机，包括全身性炎症反应， 其功能障碍与术后ir妄的发生率和严重程度有关。尚不清楚是否急性 昼夜节律时钟系统的围手术期破坏会导致异常的全身性炎症反应 沉淀术后del妄。阐明这些动态的双向关系可能会产生新颖的 预测性生物标志物和疗法以降低ir妄风险。 我们最近验证了使用转录组数据的机器学习算法Timesignature（TS） 从全血到测量一组老年人的昼夜节律转录时间。可以使用TS 确定转录组角或内部转录时间之间差异的大小 和一个人的血液采样时间。在此提案中，我们旨在确定 老年人队列中转录组角，全身炎症和ir妄严重程度的变化 进行选修心脏手术。中心假设是通过ir妄严重程度分层的患者将 昼夜节律和全身性炎症表现出明显的纵向分子模式。 在AIM 1中，我们将确定通过ir妄严重程度分层的患者是否表现出明显的纵向模式 围手术期连续性的转录组角。通过ir妄严重性分层的老年人将经历 在三个围手术期的时间点上对转录组角的连续测量：在心脏手术前一天， 在术后日（POD）1和POD 4。在AIM 2中，我们将评估是否合并蛋白质组学生物标志物 数据增强了del妄严重性组之间的纵向模式。来自AIM的患者 1将对与急性炎症有关的全面蛋白质生物标志物进行连续测量 和神经生物学损伤。该提议的贡献很重要，因为它代表了关键的第一步 在围手术期间，在建立分子昼夜节律干扰的临床相关性时。 拟议的研究具有创新性，因为它将将当前的ir妄研究范式转移到 基于精确的方法非常适合接受大手术的住院和批判性的老年人。