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.

项目摘要 纤维肌痛是一种慢性肌肉骨骼疼痛障碍，对生活质量和 对女性有很大的偏见。作为患者的靶向治疗剂的发展迫切需要 对当前的治疗剂没有反应。女性慢性肌肉疼痛的患病率明显更大 建议在其发育和维持的病理生理学中具有女性偏见的机制。最近的 关于慢性疼痛信号传导神经免疫传播的文献有性发散 机制；但是，几乎没有研究评估免疫细胞中的细胞代谢如何 调节疼痛处理。该提案的F99阶段的研究计划将测试特定 假设慢性肌肉疼痛的维持是由单核细胞性别特异性差异介导的 使用小鼠模型激活和代谢，其中单核细胞代谢受到删除的调节 肝激酶B1（LKB1），一种代谢激酶。抗炎功能在代谢上要求得多 而不是促炎功能，因此这些细胞将减少抗炎激活。我们期待 在慢性肌肉疼痛期间，没有LKB1的单核细胞具有放大的促炎表型 通过男性和女性的独特翻译曲线维护。评估疼痛行为，RNA 测序，流式细胞术和细胞代谢测定将允许鉴定表型变化 在周围单核细胞中，驱动慢性肌肉疼痛的发育和维持。工作和 在该提案的F99阶段描述将进一步了解我们对性二态机制的理解 免疫代谢作为慢性肌肉疼痛的驱动力，并为有针对性的发展提供了方向 减少慢性肌肉疼痛对患者生活质量的影响的治疗方法。 K00阶段的重点 将研究使用神经影像学和 扩大免疫学和计算生物学方面的技能。该提议的最终目标是准备 为了过渡到研究机构神经科学的教师职位，作为独立翻译 神经免疫学家特别关注慢性肌肉疼痛中的性偏见机制。