Identification of Sex Differences in Monocytes and Metabolism in the Maintenance of 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，迫切需要发展靶向治疗。 对目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 提示在其发育和维持的病理生理学中存在偏向女性的机制。近期 关于慢性疼痛信号的神经免疫通讯的文献发现了性别分化 机制；然而，几乎没有研究评估免疫细胞中的细胞新陈代谢如何 调节疼痛的处理。本提案F99阶段的研究计划将测试具体的 慢性肌肉疼痛的维持是由单核细胞的性别差异所介导的假说 小鼠模型的激活和代谢，在该模型中，单核细胞的代谢是通过缺失 肝激酶B1(LKB1)，一种代谢酶。抗炎功能对新陈代谢的要求更高 而不是促炎功能，所以这些细胞的抗炎活性会减弱。我们期待着 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，即 由男性和女性不同的翻译特征维持。疼痛行为评估，核糖核酸 测序、流式细胞术和细胞代谢分析将允许识别表型变化。 在外周单核细胞内，驱动慢性肌肉疼痛的发展和维持。这项工作和 在本提案的F99阶段中所描述的将进一步加深我们对 免疫代谢作为慢性肌肉疼痛的驱动力，为靶向发展提供方向 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 将研究纤维肌痛患者的免疫代谢和慢性疼痛，使用神经成像和 扩大免疫学和计算生物学方面的技能。这项提议的最终目的是做好准备 作为一名独立翻译，过渡到研究机构的神经科学教员职位 神经免疫学家，特别关注慢性肌肉疼痛中性别偏见机制的识别。

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.