All of the current therapies available for treating multiple sclerosis are anti-infllammatory agents that target the immune system, and there are no approved drugs that promote repair of demyelinated lesions, which is the underlying cause of neurological disability. Our long-term goal is to define how CNS lipids are regulated by changes in brain hormones and how this affects neurological disease. The overall objective in this application, which is the first step toward achieving our long-term goal, is to identify lipid-related genes that are important during remyelination and define how the lipidome changes during demyelination and remyelination. Our central hypothesis is that hormones promote myelination through transcriptional regulation of genes involved in lipid metabolism, and that regulation of lipids is critical for successful remyelination. Our hypotheses have been formulated based on studies showing that thyroid hormone regulates lipid-related genes in the brain and during oligodendrocyte progenitor cell (OPC) differentiation, which is an important step in myelination. In addition, several lipid classes including sterols and lysophosphatidic acids have been implicated in remyelination. The rationale that supports the proposed research is that it will identify lipid pathways for the development of new therapies for promoting myelin repair. The central hypothesis will be evaluated with the two following specific aims: (1) Identify lipid-related genes regulated by nuclear receptors and required for OPC differentiation; and (2) Map myelin lipid changes during remyelination. In the first aim, an OPC differentiation assay will be used to evaluate a panel of nuclear receptor ligands that have been implicated in myelination. RNA-sequencing will then be performed to identify lipid-related genes involved in OPC differentiation and membrane process extension. For the second aim, brain lipids will be isolated from an inducible conditional knockout mouse model of demyelination based on the Plp-CreERT;Myrffl/fl strain. Mass spectrometry analysis will be performed to profile the brain lipidomic changes in demyelinating and remyelinating phases of the disease course. The proposed research is innovative, in the applicant’s opinion, because two orthogonal approaches are being used to synergistically identify new lipid pathways of importance in remyelination. Upon completion of this proposed research, it is expected that one or more lipid pathways involved in CNS remyelination will be identified. This contribution is expected to be significant, because it will increase knowledge about how lipids are regulated during remyelination and may reveal a novel target for therapeutic intervention in diseases affected by demyelination. These studies will also provide necessary preliminary data for a competitive R01 grant application in the future.