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.

人类的术后恢复差异很大，而且所涉及的机制也很差 明白了。外周单核细胞和脑小胶质细胞采用的激活状态可能不利于 与术后合并症（如疼痛和谵妄）相关的炎症消退途径 恢复。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 尽管有广泛的基础和研究，但仍可充分预先确定患者手术后的疼痛或谵妄结果 转化研究。我的研究计划的首要重点是识别神经免疫 导致术后恢复变化的机制，例如疼痛、认知和 抑郁症，考虑到年龄和性别。我们的方法将结合创新技术和 相关的临床前实验模型来研究单核细胞/小胶质细胞参与 术后恢复，重点关注疼痛和谵妄。在过去的5年里，我们已经开始阐明 年龄和性别如何影响涉及疼痛和炎症认知缺陷的神经炎症过程 刺激，类似手术的情况。我们和其他人已经确定，随着年龄的增长，疼痛和认知状态会发生变化 与免疫系统的“启动”有关，而不是“当前”状况。以我们目前的工作为基础， 未来五年我们建议： 1）建立临床相关的术后评估体系来评估 啮齿动物疼痛和谵妄的恢复阶段。评估体重减轻、身体状况的初步实验 男性和女性年轻和老年群体的温度和动态运动将设定一个 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） 调节神经元处理是治疗发展的必要步骤。我们将应用基因组学 将“核糖体亲和纯化”（TRAP）转化为外周单核细胞和脑小胶质细胞的方法。一个 TRAP 的主要优势是能够识别细胞特异性的“功能转录组”。这种方法利用 转基因小鼠并捕获蛋白质合成过程中位于核糖体上的主动翻译 mRNA。这 允许使用测序技术对翻译的 RNA 进行定量。创新的一个重要点和 对我们提出的工作的影响是免疫细胞中功能性 mRNA 在衰老、性和手术中的身份 将被揭晓。最令人感兴趣的是已知可促进疼痛和/或炎症细胞因子的调节 手术后出现谵妄。所提出的工作具有高度创新性，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方向 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。我们的愿景是将行为和定量、细胞类型特异性结合起来 转录组学对术后观察到的不同恢复结果进行直观描述。