Understanding role of circadian disruption in pathogenesis of MS

摘要 可以想象，多发性硬化症(MS)的疾病进展是由有助于 重新髓鞘形成失败，并确定这些机制是开发新的治疗方法的关键。当前 对多发性硬化症患者的治疗在治疗严重影响患者生活质量的继发性并发症方面无效 生活，如睡眠和疲惫。这项工作的长期目标是发现新的战略来促进 多发性硬化症患者的髓鞘再生。虽然昼夜节律和/或睡眠紊乱在多发性硬化症患者中很常见，但它们在 在多发性硬化症的背景下，影响髓鞘再生的过程是未知的。这项研究的总体目标是 因此，要了解昼夜节律紊乱可能改变重新髓鞘形成和 多发性硬化症的疾病进展这些研究的基本原理源于初步观察到的昼夜节律 在动物模型中，节律紊乱(CRD)与神经功能障碍相关，并导致再髓鞘功能障碍。 我们的初步数据表明，关键的昼夜节律调节因子BMal1是由少突胶质细胞表达的 小鼠和多发性硬化症大脑中的谱系细胞，对重新髓鞘形成至关重要。根据这些观察，我们的中央 假说是“BMal1介导的昼夜节律紊乱导致重新髓鞘形成失败和骨髓瘤的进展。 MS的病程“。这一假设将通过三个具体目标进行检验。特定目标1将评估 多发性硬化睡眠障碍患者CRD基因多态性与多发性硬化脑组织的关系 多发性硬化症患者脑部磁共振成像和病理改变与KEY基因多态性的关系 昼夜节律基因。由于人体研究不能被操纵，我们建议对相关发现进行检验 来自人类研究，使用睡眠剥夺和脱髓鞘/重新髓鞘形成的动物模型。特定目标 2将讨论昼夜节律的变化是否会导致动物模型中的重新髓鞘形成缺陷。特定目标 3将研究BMal1的细胞特异性丢失和获得对CRD介导的重新髓鞘形成的影响 缺陷。这一提议在概念上是创新的，因为我们调查了以前未探索过的 昼夜节律紊乱与重新髓鞘形成和少突胶质细胞生物学。从技术上讲，这种方法 创新是因为我们建议使用睡眠中断的多发性硬化症患者样本、多发性硬化症尸检组织和动物 少突胶质细胞和少突胶质祖细胞特异性缺失和过表达的模型 关键的昼夜节律基因BMal1。多发性硬化症治疗的未来在于确定更多的治疗靶点 以及开发更全面的组合策略。这项工作将对 多发性硬化症研究领域，因为它将揭示昼夜节律紊乱和髓鞘修复失败之间的联系，以及在 未来将指导针对重新设置昼夜节律的药物的使用，以改善临床结果 对于多发性硬化症患者。

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 patients.