Delirium, Acute Inflammation, and Rhythmic Transcriptomics (DART)

项目总结 老年人术后精神错乱给患者、家属和医院带来了巨大的负担 系统 与美国的成本相比， 320亿美元。尽管如此，术后的病理生理学 精神错乱仍然知之甚少，也没有治疗方法。 生物钟系统的紊乱可能是术后精神错乱的原因之一。生物钟 系统协调大多数生理过程的时间，包括全身炎症反应， 其功能障碍与术后精神错乱的发生率和严重程度有关。目前尚不清楚是否存在急性、 围手术期生物钟系统的紊乱导致异常的全身性炎症反应 导致术后精神错乱。阐明这些动态的、双向的关系可能会产生新的 降低精神错乱风险的预测性生物标志物和治疗方法。 我们最近验证了一种机器学习算法TimeSignature(TS)，它使用转录数据 从全血中测量一组老年人的内部昼夜节律转录时间。可以使用TS 确定转录角度，或内部转录时间之间差异的大小 以及个体采血的真实时间。在这个提案中，我们的目标是确定时间上的联系 一组老年人的转录角度、全身性炎症和妄想严重程度的变化 正在接受择期心脏手术。中心假设是根据精神错乱的严重程度分层的患者将 在围手术期表现出明显的昼夜节律和全身性炎症的纵向分子模式。 在目标1中，我们将确定根据妄想严重程度分层的患者是否表现出明显的纵向模式 整个围手术期的转录角。根据精神错乱的严重程度分层的老年人将经历 连续测量围手术期三个时间点的转录角：心脏手术前一天， 术后第1天和第4天。在目标2中，我们将评估是否加入蛋白质组生物标记物 数据增强了对精神错乱严重程度组的纵向模式的区分。来自AIM的相同患者 1将接受与急性炎症相关的一系列蛋白质生物标志物的系列检测 和神经生物损伤。这项提议的贡献是重大的，因为它是关键的第一步。 确定围手术期分子昼夜节律紊乱的临床相关性。 这项拟议的研究具有创新性，因为它将把目前的精神错乱研究范式转变为 基于精确的方法非常适合接受大手术的住院和危重老年人。

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.