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; 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.

抽象的 可以想象，多发性硬化症（MS）的疾病进展是由有助于的机制驱动的 透明度失败和对这些机制的识别对于开发新型疗法至关重要。当前的 MS患者的疗法无效治疗次要并发症，这显着影响 生活，例如睡眠和疲劳。这项工作的长期目标是发现新的策略以促进 MS患者的再髓系。虽然MS患者常见昼夜节律和/或睡眠中断，但它们在 在MS的背景下影响再髓的过程是未知的。这项研究的总体目标 因此，是要了解昼夜节律破坏可能会改变re髓和的机制 MS疾病进展。这些研究的基本原理，从昼夜节学的初步观察中 节奏破坏（CRD）与神经系统定义相关，并导致动物模型中的再髓衰竭。 我们的初步数据表明，关键的昼夜节律BMAL1由少突胶质细胞表示 小鼠和MS大脑中的谱系细胞，对于remer骨至关重要。基于这些观察，我们的中心 假设是“ BMAL1介导的昼夜节律破坏有助于再生失败和进展 MS的疾病课程”。该假设将通过三个特定目的检验。具体目标1将评估 MS睡眠障碍患者和MS脑组织的CRD基因多态性的贡献 将MS大脑的磁共振成像和病理与钥匙中的遗传多态性相关联 昼夜节律基因。由于人类研究不适合操纵，我们建议测试相关结果 从人类研究使用睡眠剥夺和脱髓鞘/再生的动物模型。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再生缺陷。具体目标 3将研究细胞特异性损失和BMAL1的增益对CRD介导的再髓系的后果 缺陷。该建议在概念上是创新的，因为我们研究 昼夜节律的破坏以及透明式和少突胶质生物学的过程。从技术上讲，方法是 创新性，因为我们建议使用MS患者样品，患有睡眠破坏，MS尸检组织和动物 具有少突胶质细胞和少突胶质细胞祖细胞特异性缺失和过表达的模型 关键昼夜节律基因，BMAL1。 MS治疗的未来在于识别其他治疗靶标 并制定更全面的组合策略。这项工作将对 MS研究领域，因为它将揭示昼夜节律的破坏与髓磷脂维修失败之间的联系 未来将指导使用用于重置昼夜节律以改善临床结果的药物 适用于MS患者。