Abstract: Multiple sclerosis (MS) is a neurodegenerative, autoimmune disease characterized by the destruction of the neuron-surrounding myelin sheath. Myelin has the double duty of assisting with the propagation of nerve impulses and shielding neurons from external harm. Once immune cells strip the neuron of myelin, exposed axons begin to decay, leading to the debilitating symptoms of MS. Currently approved therapies for MS are aimed at inhibiting the immune response and do not address the need to promote myelin repair. Development of therapeutics that would activate myelination and prevent the irreversible changes associated with neuronal death is paramount to improving the quality of life and survival of MS patients. The central nervous system (CNS) contains oligodendrocyte precursor cells (OPCs) that have the potential to differentiate into mature oligodendrocytes and remyelinate denuded axons, a process that is affected in MS patients. Our long-term goal is to develop new MS treatments that halts neurodegeneration by promoting myelin repair, affording a potentially curative drug. The innovation driving this proposal is an in silico screen that allowed discovery of a molecule that drives OPC differentiation in vitro. The efficacy of this compound was validated in a mouse model of experimental autoimmune encephalomyelitis (EAE, an animal model of MS). Our goal in this proposal is to shed light on the novel mechanism of action of this agent and identify chemotypes that activate remyelination. Guided by strong preliminary evidence, this goal will be achieved by pursuing two specific aims: 1) discover the receptor/protein target of this agent, which is key to OPCs differentiation, and 2) develop our hit compound into drug-like molecules with efficacy and potency suitable for testing in animal models of MS. Our approach is significant because it will lead to identification of protein targets in MS that promote myelination and new therapeutics with novel modes of action. Our investigations will lead to fundamental advances in understanding the regulation of myelination.