PROJECT SUMMARY Failure to regenerate myelin in multiple sclerosis (MS) contributes to progressive axonal loss and accumulated disability. We have found that the pharmacological inhibition of Slc7a5, a large neutral amino acid transporter, significantly increases a cluster of microglia/macrophages associated with regeneration in demyelinated lesions, leading to enhanced remyelination in mice. How Slc7a5 inhibition influences microglial activity and impact the lesion microenvironment during remyelination remains unknown. Here, we hypothesize that Slc7a5 inhibition shfits the activation state of microglial cells in demyelinated lesions towards a pro-regenerative state, thereby increasing oligodendrocyte differentiation and the remyelination process. To this end, we will examine the impact of conditional Slc7a5 deletion in microglia and macrophages on oligodendrocyte and microglia/macrophage responses during remyelination (Aim 1), examine the metabolic and proteomic composition of pro-regenerative myeloid cells from demyelinated lesions of mice under Slc7a5 loss-of-function (Aim 2), and examine candidate microglia/macrophage expressed factors in in the regulation of remyelination under Slc7a5 deletion (Aim 3). The results of this study will reveal new mechanisms of microglia-oligodendrocyte interaction during remyelination, and potentially lead to new therapeutic strategies targeting microglial plasticity in demyelinated lesions to improve remyelination in MS.