Mechanisms involved in postoperative recovery: a focus on pain, delirium, and neuroinflammation

术后恢复的机制：关注疼痛、谵妄和神经炎症

• 批准号: 10501025
• 负责人: Michael D Burton
• 金额: $ 37.58万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10501025
• 关键词: Accounting; Adopted; Affinity Chromatography; Age; Aging; Behavioral; Body Temperature; Body Weight decreased; Brain; Cells; Clinical; Cognition; Cognitive; Cognitive deficits; Delirium; Elderly; Experimental Models; Female; Financial Hardship; Genomics; Goals; Healthcare; Home; Human; Immune; Immune system; Inflammation; Inflammatory; Intuition; Mental Depression; Messenger RNA; Methods; Microglia; Molecular; Movement; Neuroimmunomodulation; Neurons; Neurosciences; Operative Surgical Procedures; Outcome; Pain; Pathway interactions; Patients; Peripheral; Phase; Postoperative Pain; Postoperative Period; Process; Protein Biosynthesis; RNA; Recovery; Regulation; Research; Research Personnel; Resolution; Ribosomes; Rodent; Stimulus; System; Techniques; Transgenic Mice; Translating; Variant; Vision; Work; age group; cell type; clinically relevant; comorbidity; cytokine; experimental study; innovation; innovative technologies; insight; interest; male; monocyte; neuroinflammation; novel therapeutic intervention; postoperative delirium; postoperative recovery; pre-clinical; programs; public health relevance; sex; therapeutic development; transcriptome; transcriptomics; translational study

Postoperative recovery in humans varies over a large range and the mechanisms involved are poorly understood. Peripheral monocytes and brain microglia adopt activation states that can be detrimental to inflammation resolution pathways involved in postoperative comorbidities like pain and delirium that impact recovery. The range of activation states correlates to the range of postoperative recovery possibilities observed in both clinical and experimental settings. This potentially explains the inability of researchers and clinicians to adequately predetermine a patient’s pain or delirium outcome after surgery, despite extensive basic and translational studies. The overarching focus of my research program is to identify neuroimmune mechanisms that contribute to variations in postoperative recovery, such as, pain, cognition, and depression, accounting for age and sex. Our approach will combine innovative technologies and relevant pre-clinical experimental models to investigate monocyte/microglia involvement in postoperative recovery with a focus on pain and delirium. In the past 5 years, we have begun to elucidate how age and sex influences neuroinflammatory processes involved in pain and cognitive deficits to inflammatory stimuli, a condition like surgery. We and others have determined that changes in pain and cognitive states in age is related to “priming” of the immune system and not “current” conditions. Building from our current work, over the next five years we propose to: 1) Build a clinically relevant postoperative assessment system to evaluate recovery phases in the context of pain and delirium in rodents. Initial experiments to assess weight loss, body temperature, and ambulatory movement in male and female young and advanced age groups will set an important premise. 2) Determine how age and sex influence monocytes (pain) and microglia (delirium) to modulate neuronal processing is an imperative step toward therapeutic development. We will apply the genomics method of “translating ribosome affinity purification”, (TRAP) to peripheral monocytes and brain microglia. A major strength of TRAP is the ability to identify a cell-specific “functional transcriptome”. This approach utilizes transgenic mice and captures actively translating mRNAs located on ribosomes during protein synthesis. This allows for quantification of translated RNAs using sequencing techniques. An important point of innovation and impact for our proposed work is that the identity of functional mRNAs in immune cells in aging, sex, and surgery will be revealed. Of most interest will be regulation of inflammatory cytokines known to promote pain and/or delirium after surgery. The work proposed is highly innovative because it integrates advanced methods to resolve our understanding of postoperative pain and delirium, to eventually move these molecular insights toward new therapeutic strategies, which aligns with the growing emphasis on human molecular neuroscience in my home department and research center. Our vision is to integrate behavioral and quantitative, cell-type specific transcriptomics to create intuitive descriptions of the diverse recovery outcomes observed postoperatively.

人类术后恢复的差异很大，所涉及的机制也很差 明白外周单核细胞和脑小胶质细胞采取激活状态，这可能不利于 炎症消退途径参与术后并发症，如疼痛和谵妄， 复苏激活状态的范围与观察到的术后恢复可能性的范围相关 在临床和实验环境中。这可能解释了研究人员和临床医生无法 充分预先确定患者的疼痛或谵妄手术后的结果，尽管广泛的基础和 翻译研究我的研究计划的首要重点是确定神经免疫 导致术后恢复变化的机制，如疼痛、认知和 抑郁症，年龄和性别。我们的方法将结合联合收割机创新技术和 相关的临床前实验模型，以研究单核细胞/小胶质细胞参与 术后恢复，重点是疼痛和谵妄。在过去的5年里，我们已经开始阐明 年龄和性别如何影响疼痛和炎症认知缺陷中涉及的神经炎症过程 刺激，像手术一样的条件。我们和其他人已经确定，随着年龄的增长，疼痛和认知状态的变化 与免疫系统的“启动”有关，而与“当前”条件无关。从我们目前的工作中， 未来五年，我们建议：1）建立一个临床相关的术后评估系统， 啮齿动物疼痛和谵妄背景下的恢复阶段。初步实验，以评估体重减轻，身体 在男性和女性的年轻和先进的年龄组的温度和走动运动将设置一个 重要前提。2)确定年龄和性别如何影响单核细胞（疼痛）和小胶质细胞（谵妄）， 调节神经元加工是朝向治疗发展的必要步骤。我们将运用基因组学 方法“翻译核糖体亲和纯化”，（TRAP）的外周单核细胞和脑小胶质细胞。一 TRAP的主要优势是鉴定细胞特异性“功能转录组”的能力。该方法利用 转基因小鼠和捕获积极翻译mRNA位于核糖体蛋白质合成过程中。这 允许使用测序技术定量翻译的RNA。创新的一个重要方面， 对我们所提出的工作的影响是，在衰老、性别和手术中免疫细胞中功能性mRNA的身份 将被揭露。最感兴趣的将是已知促进疼痛和/或炎症的炎性细胞因子的调节。 手术后精神错乱所提出的工作具有很强的创新性，因为它集成了先进的方法来解决 我们对术后疼痛和谵妄的理解，最终将这些分子见解推向新的 治疗策略，这与我家对人类分子神经科学的日益重视相一致 部门和研究中心。我们的愿景是整合行为和定量，细胞类型特异性 转录组学来创建术后观察到的不同恢复结果的直观描述。