PROJECT SUMMARY/ABSTRACT Multiple sclerosis (MS) is an autoimmune disease that affects nearly 3 million people. MS manifests when the immune system attacks myelin, the insulating sheath around nerve fibers, and myelin producing cells in the central nervous system (CNS). As a result, MS patients suffer from motor, sensory and cognitive deficits. The most common form of MS, relapse-remitting MS (RRMS), is characterized by repetitive cycles of disease and recovery. Tragically, if left untreated, two-thirds of RRMS patients progress to secondary progressive MS (SPMS), characterized by continuous disease progression and irreparable CNS damage. To date, the cause of MS is unclear and there is no cure. To identify potential targets for therapeutic interventions, it is critical to define the cellular and molecular mechanisms underlying MS disease progression. Microglia, long-lived CNS immune cells, have been shown to respond to disease by altering their morphology and gene activity. Preliminary data have shown that this acquired disease-associated microglia (DAM) phenotype is responsible for clearing myelin debris to facilitate remyelination, indicating that DAM could be harnessed to protect against MS progression. To understand the cellular programming underlying microglia function in the context of MS, this project aims to both define the gene specific gene signature of DAM, and define how the function of these cells is affected by repeated activation, such as occurs in relapse- remitting MS. By revealing the mechanism and functional impact of microglia reactivation, this proposal will directly address an outstanding question in the field about how long-term activation of microglia may contribute to MS disease progression. Importantly, microglia, and more specifically, the DAM phenotype appears in chronic neurodegenerative diseases. Therefore, understanding the long-term changes of chronically activated microglia in this project can provide new insights for other disease models in which microglia have been implicated. Upon completion of the proposed project aims, this fellowship would have supported my technical and professional development. Specifically, by completing this project, I would have developed independence in designing, executing, and analyzing experiments to understand epigenetic reprograming of microglia, as well as learning to use a novel model system for studying microglia activation. Additionally, I would have developed my oral and written scientific communication skills. Ultimately, support from this fellowship will help me achieve my long-term goal of becoming a tenured faculty member at an R1 institution.