Advancing the Understanding of Postoperative Delirium Mechanisms via Multi-Omics

通过多组学促进对术后谵妄机制的理解

基本信息

批准号：
9204773
负责人：
TOWIA A. LIBERMANN
金额：
$ 60.25万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-15 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9204773
关键词：
Acute Acute-Phase Proteins Address Aging Biological Biological Markers Blood Blood - brain barrier anatomy Cerebrospinal Fluid Clinical Clinical Management Cognitive Cohort Studies Complex Confusion Data Set Delirium Dependence Development Diagnosis Disease Elderly Enzyme-Linked Immunosorbent Assay Functional disorder Funding Goals Health Care Costs Hip region structure Impaired cognition Incidence Inflammation Inflammatory Inflammatory Response Intervention Knowledge Lead Link Lipids Mass Spectrum Analysis Measures Membrane Methods Modeling Monitor NIH Program Announcements National Institute on Aging Neuronal Injury Operative Surgical Procedures Orthopedic Surgery procedures Orthopedics Participant Pathway interactions Patients Plasma Plasma Proteins Postoperative Period Preventive Proteins Proteomics Recovery Research Sampling Schedule Severities Specimen Syndrome System Systems Biology Translating Work base biobank biomarker discovery clinical Diagnosis cognitive change cohort cost cytokine design experience functional disability improved metabolomics mortality neuroinflammation neuron loss postoperative delirium predictive signature prevent programs protein metabolite public health relevance response secondary analysis stressor

项目摘要

DESCRIPTION (provided by applicant): Delirium complicates 15-53% of major surgery in older adults, resulting in 2-20 fold increased mortality, long term cognitive and functional impairment, and increased healthcare costs. Yet, delirium remains a wholly clinical diagnosis; its pathophysiology remains largely unknown, with no biomarkers to guide its diagnosis or management. Over the past 4.5 years, we conducted the "Biomarker Discovery for Delirium" project within a National Institute on Aging (NIA) program project that funded the SAGES (Successful Aging after Elective Surgery) study. Using the SAGES plasma biorepository and state-of-the-art approaches, including proteomics, we found that pro-inflammatory cytokines, acute phase reactants, and neuronal injury markers are consistently elevated in delirious patients relative to matched controls. These results support a model for delirium in which a predisposing, systemic pre-inflammatory state results in a dysfunctional response to a stressor (major surgery), leading to blood brain barrier breakdown, microglial activation, neuro-inflammation, neuronal injury and death. Responding to NIA Program Announcement PA-13-168 "Secondary analysis of existing data sets and stored biospecimens to address clinical aging research questions", we now propose a new set of Specific Aims with no scientific or budgetary overlap with our P01-funded project. We will leverage specimens from SAGES, and an independent orthopedic cohort, HiPOR (Healthier Postoperative Recovery) that collected and stored both plasma and preoperative cerebrospinal fluid (CSF). We will apply cutting edge systems level "Omics" methods to define delirium signatures that integrate proteins, lipids, and metabolites from both plasma and CSF. We will seek to confirm and further elucidate the dysfunctional inflammation pathophysiological model described above, and probe additional mechanisms for delirium that might interact with, or be independent of the above pathways. In this context, we propose the following Specific Aims: Aim 1: Define and validate a plasma protein signature for delirium Aim 2: Define plasma lipid and metabolite delirium signatures, integrate with the protein signature, and validate this integrated signature across the SAGES cohort and in the independent HiPOR sample Aim 3: Define an integrated CSF-based protein, lipid, and metabolite signature for delirium. Impact: Our immediate goals are to develop integrated (protein, metabolite, lipid) plasma and CSF-based biomarker signatures for delirium using banked specimens from two cohort studies of older orthopedic patients. We will further elucidate the inflammatory pathway described above and uncover others through the proposed Aims, which will fundamentally advance our knowledge of the pathophysiology of delirium. Ultimately, our goal is to translate our findings to the bedside through improved methods of diagnosis and monitoring of delirium, and though the design of targeted, pathophysiologically based interventions. Therefore, the long term impact of the proposed work will be to transform clinical management of this common, morbid, and costly syndrome.

描述（由申请人提供）：谵妄使 15-53% 的老年人大手术复杂化，导致死亡率增加 2-20 倍、长期认知和功能障碍以及医疗费用增加。然而，谵妄仍然是一种完全的临床诊断；其病理生理学在很大程度上仍然未知，没有生物标志物来指导其诊断或治疗在过去 4.5 年里，我们在国家衰老研究所内开展了“谵妄生物标志物发现”项目。 (NIA) 资助 SAGES（选择性手术后成功衰老）研究的项目使用 SAGES 血浆生物库和最先进的方法（包括蛋白质组学），我们发现促炎细胞因子、急性期反应物和神经元。与对照患者相比，精神错乱的相关患者的损伤标志物持续升高。这些结果支持了一种精神错乱模型，其中易感的全身性炎症前状态导致对应激源（主要）的功能障碍反应。手术），导致血脑屏障破坏、小胶质细胞激活、神经炎症、神经元损伤和死亡，响应 NIA 计划公告 PA-13-168“对现有数据集和存储的生物样本进行二次分析，以解决临床衰老研究问题”，我们现在提出了一套新的具体目标，与我们的 P01 资助项目没有科学或预算重叠，我们将利用 SAGES 和独立骨科队列 HiPOR 的样本。（更健康的术后恢复）收集并储存血浆和术前脑脊液（CSF），我们将应用尖端的系统级“组学”方法来定义整合血浆和脑脊液中的蛋白质、脂质和代谢物的谵妄特征。确认并进一步阐明上述功能失调的炎症病理生理学模型，并探讨可能与上述途径相互作用或独立的其他机制。在这种情况下，我们提出以下具体建议。目标：目标 1：定义并验证谵妄的血浆蛋白特征目标 2：定义血浆脂质和代谢物谵妄特征，与蛋白质特征整合，并在 SAGES 队列和独立 HiPOR 样本中验证此整合特征目标 3：定义基于脑脊液的蛋白质、脂质和代谢物特征的谵妄影响：我们的近期目标是开发基于血浆和脑脊液的综合生物标志物（蛋白质、代谢物、脂质）。我们将使用来自老年骨科患者的两项队列研究的样本来研究谵妄的特征，我们将进一步阐明上述炎症途径，并通过拟议的目标揭示其他途径，这将从根本上增进我们对谵妄病理生理学的了解。通过改进谵妄的诊断和监测方法，并通过设计有针对性的、基于病理生理学的干预措施，将我们的发现转化为临床。因此，拟议工作的长期影响将是改变临床。管理这种常见、病态且代价高昂的综合症。