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: 10689302
• 负责人: Michael D Burton
• 金额: $ 38.27万
• 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/10689302
• 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 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.

人类的术后恢复在较大的范围内各不相同，涉及的机制很差 理解齿。外围单核细胞和脑小胶质细胞采用激活状态，可以确定为 术后合并症等炎症途径（如疼痛和del妄）影响 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对 手术后，充分预先确定患者的疼痛或ir妄结局，绝望的基本和 翻译研究。我的研究计划的总体重点是确定神经免疫 导致术后恢复差异的机制，例如疼痛，认知和 抑郁症，会计年龄和性别。我们的方法将结合创新技术和 相关的临床前实验模型，研究单核细胞/小胶质细胞参与 术后恢复，专注于疼痛和del妄。在过去的5年中，我们开始阐明 年龄和性别如何影响疼痛和认知缺乏涉及炎症的神经炎症过程 刺激，诸如手术之类的疾病。我们和其他人确定年龄的疼痛和认知状态的变化 与免疫系统的“启动”而不是“当前”条件有关。从我们目前的工作中建立 接下来的五年我们建议：1）建立临床相关的术后评估系统以评估 在啮齿动物中疼痛和ir妄的背景下的恢复阶段。评估体重减轻的初始实验，身体 男性和女性年轻和高龄群的温度和卧床运动将设定 重要的前提。 2）确定年龄和性别如何影响单核细胞（疼痛）和小胶质细胞（delirium） 调节神经元加工是迈向治疗发展的必要步骤。我们将应用基因组学 “翻译核糖体亲和力纯化”，（TRAP）为周围单核细胞和脑小胶质细胞的方法。一个 陷阱的主要优势是能够识别细胞特异性的“功能转录组”的能力。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mRNA积极翻译。这 允许使用测序技术定量翻译的RNA。创新和 对我们提出的工作的影响是，衰老，性别和手术中免疫细胞中功能性mRNA的身份 将被揭示。最感兴趣的是调节已知会促进疼痛和/或的炎症细胞因子 手术后的del妄。提出的工作具有很高的创新性，因为它整合了高级方法来解决 我们对术后疼痛和del妄的理解，最终将这些分子见解转向新 治疗策略，这与我家中人类分子神经科学的越来越重视 部门和研究中心。我们的视野是整合行为和定量的细胞类型特异性 转录组学以创建对潜水员恢复结果的直观描述。

项目成果

Anti-hyperalgesic and anti-inflammatory effects of 4R-tobacco cembranoid in a mouse model of inflammatory pain.

• DOI: 10.1186/s12950-023-00373-8
• 发表时间: 2024-01-24
• 期刊: JOURNAL OF INFLAMMATION-LONDON
• 影响因子: 5.1
• 作者: Rivera-Garcia, Luis G.;Francis-Malave, Adela M.;Castillo, Zachary W.;Uong, Calvin D.;Wilson, Torri D.;Ferchmin, P. A.;Eterovic, Vesna;Burton, Michael D.;Carrasquillo, Yarimar
• 通讯作者: Carrasquillo, Yarimar