Understanding role of circadian disruption in pathogenesis of MS

了解昼夜节律紊乱在多发性硬化症发病机制中的作用

• 批准号: 10574570
• 负责人: Ranjan Dutta
• 金额: $ 47.08万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10574570
• 关键词: ARNTL gene; Acute; Address; Affect; Animal Model; Autopsy; Biology; Brain; Cell Lineage; Cell physiology; Cells; Central Nervous System; Circadian Dysregulation; Circadian Rhythms; Clinical; Cuprizone; Darkness; Data; Defect; Demyelinations; Disease; Disease Management; Disease Progression; Drug Side Effects; Drug usage; Event; Failure; Fatigue; Frequencies; Future; General Population; Genes; Genetic Polymorphism; Goals; Human; Knowledge; Lead; Lesion; Light; Link; Magnetic Resonance Imaging; Mediating; Mediator; Mission; Molecular; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Myelin; National Institute of Neurological Disorders and Stroke; Nervous System Physiology; Nervous System control; Neurologic Deficit; Oligodendroglia; Outcome; Pathogenesis; Pathogenicity; Pathology; Patients; Pharmaceutical Preparations; Process; Public Health; Quality of life; Research; Role; Sampling; Sleep; Sleep Deprivation; Sleep Disorders; Sleep disturbances; Specificity; Testing; Therapeutic; Tissue Model; Transcriptional Regulation; Work; brain tissue; burden of illness; chronic demyelination; circadian; circadian pacemaker; combinatorial; disability; experience; illness length; improved; inflammatory milieu; innovation; mouse model; multiple sclerosis patient; multiple sclerosis treatment; novel; novel therapeutics; oligodendrocyte lineage; oligodendrocyte precursor; oligodendrocyte progenitor; overexpression; precursor cell; prevent; reduce symptoms; remyelination; repaired; sleep pattern; stem; stem cells; therapeutic target; therapy development

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.

摘要 多发性硬化症（MS）的疾病进展可能是由以下机制驱动的： 髓鞘再生失败，这些机制的鉴定是开发新疗法的关键。电流 MS患者的治疗在治疗继发性并发症方面是无效的，这些并发症显著影响MS患者的治疗质量。 如睡眠和疲劳。这项工作的长期目标是发现新的战略，以促进 MS患者的髓鞘再生。虽然昼夜节律和/或睡眠中断在MS患者中很常见，但它们在MS患者中的作用可能与MS患者的生理节律有关。 在MS的背景下影响髓鞘再生的过程是未知的。本研究的总体目标 因此，了解昼夜节律紊乱可能改变髓鞘再生的机制， 多发性硬化症的疾病进展。这些研究的理由源于初步观察，即昼夜节律 节律中断（CRD）与神经缺陷相关，并导致动物模型中的髓鞘再生失败。 我们的初步数据表明，关键的昼夜节律调节因子Bmal 1由少突胶质细胞表达， 在小鼠和多发性硬化症大脑中的谱系细胞，并且对于髓鞘再生至关重要。根据这些观察，我们的中央 一种假说认为，“Bmal 1介导的昼夜节律破坏有助于髓鞘再生失败和 疾病在MS”。这一假设将通过三个具体目标进行检验。具体目标1将评估 CRD基因多态性在伴有睡眠障碍的MS患者和MS脑组织中的作用， 多发性硬化症脑的磁共振成像和病理学与遗传多态性相关， 昼夜节律基因由于人类研究不容易被操纵，我们建议测试相关的发现 来自于使用睡眠剥夺和脱髓鞘/髓鞘再生的动物模型的人类研究。具体目标 2将解决昼夜节律的变化是否会导致动物模型中的髓鞘再生缺陷。具体目标 3将研究细胞特异性Bmal 1丢失和获得对CRD介导的髓鞘再生的影响 缺陷这个建议在概念上是创新的，因为我们调查了一个以前未探索的联系， 昼夜节律破坏和髓鞘再生过程以及少突胶质细胞生物学。该方法在技术上 创新，因为我们建议使用具有睡眠中断的MS患者样品、MS尸检组织和动物 少突胶质细胞和少突胶质细胞祖细胞特异性缺失和过度表达的模型， 关键昼夜节律基因Bmal 1。多发性硬化症治疗的未来在于确定其他治疗靶点 以及开发更全面的组合策略。这项工作将产生重大影响， 因为它将揭示昼夜节律破坏和髓鞘修复失败之间的联系， 未来将指导药物的使用，旨在重新设定昼夜节律，以改善临床结果 MS患者。