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.