Identification of Sex Differences in Monocytes and Metabolism in the Maintenance of Chronic Muscle Pain

识别单核细胞的性别差异和维持慢性肌肉疼痛的代谢

• 批准号: 10541680
• 负责人: Melissa Elizabeth Lenert
• 金额: $ 4.4万
• 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: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10541680
• 关键词: Acute; Adolescent; Affect; Affinity Chromatography; American; Anti-Inflammatory Agents; Automobile Driving; Award; Back; Behavior; Behavioral; Bioinformatics; Biological Assay; Cells; Cellular Metabolic Process; Chronic; Clinical; Clinical Immunology; Clinical Research; Clinical assessments; Communication; Computational Biology; Computing Methodologies; Data; Data Set; Development; Estrous Cycle; Excision; Experimental Designs; Faculty; Female; Fibromyalgia; Flow Cytometry; Functional disorder; Goals; Gonadal Steroid Hormones; High Fat Diet; Immune; Immunology; Inflammation; Inflammatory; Institution; Intervention; Intramuscular Injections; Journals; Literature; Maintenance; Measurement; Mediating; Mentors; Mentorship; Metabolic; Metabolism; Molecular Biology; Movement; Mus; Myalgia; Neuroendocrinology; Neuroimmune; Neurosciences; Neurosecretory Systems; Oral; Output; Pain; Pain Measurement; Patient-Focused Outcomes; Patients; Peripheral; Phase; Phenotype; Phosphotransferases; Play; Population; Positioning Attribute; Pre-Clinical Model; Preparation; Prevalence; Price; Publishing; Quality of life; Research; Research Personnel; Research Project Grants; Rheumatism; Ribosomes; Role; STK11 gene; Saline; Scientist; Sex Bias; Sex Differences; Signal Transduction; Symptoms; Testing; Therapeutic; Therapeutic Intervention; Training; Translating; Translational Research; Woman; Work; adaptive immunity; base; chronic musculoskeletal pain; chronic pain; chronic pain patient; cytokine; design; fibromyalgia patients; follow-up; hormone metabolism; immunocytochemistry; improved; male; monocyte; mouse model; muscle strength; neuroimaging; new therapeutic target; novel; pain behavior; pain outcome; pain processing; pain signal; patient population; post-doctoral training; pre-clinical assessment; profiles in patients; sex; sexual dimorphism; skills; spontaneous pain; statistics; symposium; targeted treatment; transcriptome sequencing; transcriptomics; translational approach

Project Summary Fibromyalgia is a chronic musculoskeletal pain disorder that has a strong negative impact on quality of life and is strongly biased towards women. There is a dire need for the development of targeted therapeutics as patients are not responsive to current therapeutics. The significantly greater prevalence of chronic muscle pain in women suggests female-biased mechanisms in the pathophysiology of its development and maintenance. Recent literature on neuroimmune communication in chronic pain signaling have uncovered sexually divergent mechanisms; however, there are little to no studies assessing how cellular metabolism in immune cells can modulate pain processing. The research plan during the F99 phase of this proposal will test the specific hypothesis that maintenance of chronic muscle pain is mediated by sex-specific differences in monocyte activation and metabolism using a mouse model in which metabolism of monocytes is modulated by deletion of liver kinase B1 (LKB1), a metabolic kinase. Anti-inflammatory functions are much more metabolically demanding than pro-inflammatory functions, so these cells will have diminished anti-inflammatory activation. We anticipate monocytes without LKB1 have a magnified pro-inflammatory phenotype during chronic muscle pain that is maintained by distinct translational profiles in males and females. Assessment of pain behaviors, RNA sequencing, flow cytometry, and cellular metabolism assays will allow for the identification of phenotypic changes within peripheral monocytes driving the development and maintenance of chronic muscle pain. The work and described in the F99 phase of this proposal will further our understanding of sexually dimorphic mechanisms of immunometabolism as a driver of chronic muscle pain and provide direction for the development of targeted therapeutics to reduce the impact of chronic muscle pain on patient quality of life. The focus of the K00 phase will be to study immunometabolism and chronic pain in patients with fibromyalgia using neuroimaging and expanding skillsets in immunology and computational biology. The ultimate goal of this proposal is preparation for transition to a faculty position in neuroscience at a research institution as an independent translational neuroimmunologist with a special focus on identification of sex-biased mechanisms in chronic muscle pain.

项目概要 纤维肌痛是一种慢性肌肉骨骼疼痛疾病，对生活质量和健康产生强烈的负面影响 对女性有强烈的偏见。患者迫切需要开发靶向治疗方法 对当前的治疗方法没有反应。女性慢性肌肉疼痛的患病率明显更高 表明其发展和维持的病理生理学机制偏向女性。最近的 关于慢性疼痛信号传导中神经免疫通讯的文献揭示了性别差异 机制；然而，几乎没有研究评估免疫细胞中的细胞代谢如何影响 调节疼痛处理。本提案F99阶段的研究计划将测试具体 假设慢性肌肉疼痛的维持是由单核细胞的性别特异性差异介导的 使用小鼠模型进行激活和代谢，其中单核细胞的代谢通过删除 肝激酶 B1 (LKB1)，一种代谢激酶。抗炎功能对代谢的要求更高 比促炎功能强，因此这些细胞的抗炎活性会减弱。我们预计 没有 LKB1 的单核细胞在慢性肌肉疼痛期间具有放大的促炎表型，即 通过男性和女性不同的翻译特征来维持。疼痛行为评估，RNA 测序、流式细胞术和细胞代谢测定将允许识别表型变化 外周单核细胞内驱动慢性肌肉疼痛的发展和维持。工作和 该提案的 F99 阶段中描述的将进一步加深我们对性二态性机制的理解 免疫代谢作为慢性肌肉疼痛的驱动因素，并为靶向药物的开发提供方向 减少慢性肌肉疼痛对患者生活质量影响的治疗方法。 K00阶段的焦点 将利用神经影像学和方法研究纤维肌痛患者的免疫代谢和慢性疼痛 扩大免疫学和计算生物学方面的技能。该提案的最终目标是准备 作为独立翻译人员过渡到研究机构的神经科学教职 神经免疫学家，特别专注于识别慢性肌肉疼痛的性别偏见机制。