ABSTRACT Disease progression in multiple sclerosis (MS) is conceivably driven by mechanisms that contribute to remyelination failure, and identification of these mechanisms is critical for developing novel therapies. Current therapies for MS patients are ineffective at treating secondary complications that significantly impact quality of life, such as sleep and fatigue. The long-term goal of this work is to discover new strategies to facilitate remyelination in MS patients. While circadian and/or sleep disruptions are common in MS patients, their roles in affecting the process of remyelination in the context of MS are unknown. The overall objective of this study therefore is to understand the mechanisms by which circadian rhythm disruption may alter remyelination and disease progression in MS. The rationale for these studies stems from preliminary observations that circadian rhythm disruption (CRD) correlates with neurological deficits and leads to remyelination failure in animal models. Our preliminary data demonstrates that the key circadian regulator, Bmal1, is expressed by oligodendrocyte lineage cells in mice and MS brains and is critical for remyelination. Based upon these observations, our central hypothesis is that “Bmal1-mediated circadian disruption contributes to remyelination failure and progression of disease course in MS”. This hypothesis will be tested by three specific aims. Specific Aim 1 will assess the contribution of CRD gene polymorphisms in MS patients with sleep disturbances and MS brain tissues to correlate magnetic resonance imaging and pathology of the MS brains with genetic polymorphisms in key circadian genes. As human studies are not amenable to manipulation, we propose to test the correlative findings from the human studies using animal models of sleep deprivation and demyelination/remyelination. Specific Aim 2 will address whether changes in circadian rhythm lead to remyelination defects in animal models. Specific Aim 3 will investigate the consequences of cell-specific loss and gain of Bmal1 on CRD-mediated remyelination defects. This proposal is conceptually innovative because we investigate a previously-unexplored link between circadian disruption and the process of remyelination and oligodendrocyte biology. The approach is technically innovative because we propose to use MS patient samples with sleep disruption, MS autopsy tissues, and animal models with oligodendrocyte- and oligodendrocyte progenitor cell-specific deletion and overexpression of the key circadian gene, Bmal1. The future of MS therapeutics lies in the identification of additional therapeutic targets and in developing more comprehensive combinatorial strategies. This work will make a significant impact on the field of MS research because it will reveal the link between circadian disruption and myelin repair failure, and in the future will guide the use of drugs directed towards resetting the circadian rhythm to improve clinical outcome for MS pati...