Sarm1 and neural regulation of bone

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ABSTRACT Sarm1 (sterile α and TIR motif-containing protein-1) is a NADase enzyme that is highly expressed in the nervous system. The Sarm1 enzyme serves as a metabolic biosensor and is activated in response to injury, inflammation, and oxidative stress. Based on a screen of thousands of candidates in 2013, Sarm1 was identified as the central executioner of nerve axon degeneration. Since this time, Sarm1 has also been shown to modulate nerve function through regulation of MAPK signaling and metabolite turnover. In response to this pivotal discovery, Sarm1 inhibitors are now being developed for clinical management of neurodegenerative disease. Specific to bone - nerve damage, dysfunction and clinical neuropathy have all been related to fracture risk and impaired bone health in diverse conditions including spinal cord injury, anorexia, chemotherapy, multiple sclerosis and diabetes. However, the molecular mechanisms underlying these relationships remain unclear, limiting our options for therapeutic intervention. Recently, we discovered that knockout of Sarm1 prevents bone fragility in diabetic mice. Our central hypothesis is that neural Sarm1 activation restricts bone formation, leading to decreased bone mass and strength. Conversely, we hypothesize that targeted Sarm1 inhibition can be used to simultaneously promote bone and nerve health in states of chronic Sarm1 activation, such as diabetes. To test this hypothesis, we will pursue two specific aims. First, we will isolate the role of Sarm1-dependent neuropathy in the progression of skeletal disease. Second, we will target the function of Sarm1 to restore bone health in vivo. When complete, this work will define the mechanisms linking nerve damage to impaired bone health through Sarm1. We will also determine if Sarm1 inhibition is a strategy that can be used to support bone formation in settings of skeletal disease. Our long-term goal is to promote lifelong health and healthy aging by developing strategies to prevent or to reverse nerve and bone damage across diverse disease states, beginning in childhood and adolescence and continuing throughout the lifespan.