Circadian mechanisms of myelination

髓鞘形成的昼夜节律机制

基本信息

批准号：
10583197
负责人：
Erin G Valdez
金额：
$ 49.38万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10583197
关键词：
ARNTL gene Adult Alzheimer&apos s Disease Attention Attention deficit hyperactivity disorder Automobile Driving Axon Behavior Behavioral Biological Biological Models Biological Process Biology Brain Brain Diseases Brain Pathology Cell Density Cell Differentiation process Cell Lineage Cell Maintenance Cell Proliferation Cells Chronic Circadian Dysregulation Circadian desynchrony Complex Data Development Discipline of Nursing Disease Embryo Embryonic Development Encapsulated Foundations Functional disorder Genes Genetic Genetic Polymorphism Histology Hour Jet Lag Syndrome Knock-out Knockout Mice Learning Life Link Maintenance Mediating Memory Metabolic Microscopy Mitotic Modeling Molecular Morphology Motor Multiple Sclerosis Mus Myelin Nerve Degeneration Nervous System Physiology Neurodevelopmental Disorder Neurons Oligodendroglia Periodicity Phase Phenotype Physiological Pre-Clinical Model Pregnancy Process Proliferating Publishing Research Resolution Resting Phase Role Running Signal Pathway Signal Transduction Social Behavior Structure System Therapeutic Time Variant Work brain health circadian circadian pacemaker density dysmyelination emerging adult experimental study fetal in vivo individuals with autism spectrum disorder insight knock-down mouse model myelination nerve stem cell nervous system disorder neural circuit neurodevelopment novel offspring oligodendrocyte precursor optogenetics postnatal postnatal development precursor cell pregnant prenatal stem cell population transcriptome sequencing transduction efficiency white matter young adult

项目摘要

Myelin—the structure that encapsulates axons—is integral to efficient transduction of electrical signals and metabolic support of neurons. Myelin deficits have been commonly identified in a wide range of brain disorders—from neurodevelopmental to neurodegenerative—implicating dysmyelination as a prominent, but often underappreciated, feature of many neurological disorders. Similar myelin deficiencies cause decrements in attention, memory, learning, social behaviors, and motor function in preclinical models. To ultimately understand how myelination fails in these brain disorders, we first must have a comprehensive understanding of the mechanisms driving the proliferation and maintenance of myelin-forming precursor cells. Developmental myelination during pre- and post-natal life and neuronal activity-dependent adaptive myelination in adulthood both depend on oligodendrocyte precursor cells (OPCs) and their progeny, myelin-forming oligodendrocytes. There remains an unmet need to define the mechanisms mediating OPC dynamics during these two types of myelination and to reveal their roles in defining and refining circuits and behavior in development and disease. The OPC is the most abundantly mitotic cell in the brain with 70- 90% of all dividing cells at a given time being OPCs. Based on published work showing that the circadian (~24 hour) system—driven by the principal circadian molecular regulator Bmal1—regulates cell proliferation of numerous neural precursor and stem cell populations and our preliminary data confirming the necessity of Bmal1 in OPC dynamics, we aim to investigate how the circadian system regulates OPCs and consequent myelination. In addition to dysmyelination, circadian phase-shifts and polymorphisms in circadian clock genes like BMAL1 have been documented in individuals with autism, attention deficit/hyperactivity disorder, multiple sclerosis, and Alzheimer’s disease, linking disruptions in circadian machinery with pathophysiology in these disorders. We posit that circadian disruption of myelin-forming cells during development will lay the foundation for a broad range of brain pathologies. In this proposal, we aim to elevate the current biological understanding of myelination. The proposed work will investigate how the circadian system regulates myelination through 1) the development of two distinct but complimentary genetic mouse models targeting Bmal1 knock down in OPCs to probe developmental myelination 2) application of the environmental chronodisruptive chronic jet lag (CJL) model to developmental myelination, and 3) diurnal changes in neuronal activity-induced adaptive myelination. Our preliminary data establish that genetic knock down of the Bmal1-driven circadian clock in OPCs during embryonic and post-natal development results in a reduction in 1) OPC density, 2) OPC proliferation, 3) myelination, and 4) myelin-associated behaviors. A comprehensive understanding of the interplay between circadian modulation and OPC maintenance and myelination will not only inform on mechanisms of brain health but will also establish insights into potential therapeutic strategies targeting myelin-specific circadian regulatory processes in numerous brain disorders.

髓磷脂（封装轴突的结构）对于有效转导电信号和代谢至关重要神经元的支持缺陷已在多种脑部疾病中得到普遍发现——从神经发育到神经退行性——表明髓鞘发育不良是一种突出但经常被低估的疾病许多神经系统疾病的特征类似，髓鞘质缺乏会导致注意力、记忆力、学习能力下降。临床前模型中的社会行为和运动功能，最终了解髓鞘形成是如何失败的。脑部疾病，首先必须全面了解其增殖和驱动机制产前和产后期间髓磷脂形成前体细胞的维持。成年期神经元活动依赖性适应性髓鞘形成均依赖于少突胶质细胞前体细胞 (OPC) 及其后代，髓磷脂形成少突胶质细胞，定义其机制的需求仍未得到满足。在这两种类型的髓鞘形成过程中调节 OPC 动态，并揭示它们在定义和完善中的作用 OPC 是大脑中最丰富的有丝分裂细胞，具有 70- 根据已发表的研究显示，特定时间的所有分裂细胞中 90% 是 OPC（约 24 小时）。系统——由主要昼夜节律分子调节因子 Bmal1 驱动——调节许多神经细胞的细胞增殖前体细胞和干细胞群体以及我们的初步数据证实了 Bmal1 在 OPC 动力学中的必要性，我们的目标是研究昼夜节律系统如何调节 OPC 和随后的髓鞘形成。髓鞘形成障碍、昼夜节律相移和昼夜节律时钟基因（如 BMAL1）的多态性已被记录在患有自闭症、注意力缺陷/多动症、多发性硬化症和阿尔茨海默氏症的个体中疾病，将昼夜节律机制的破坏与这些疾病的病理生理学联系起来。发育过程中髓磷脂形成细胞的破坏将为广泛的脑部病理学奠定基础。在本提案中，我们的目标是提高目前对髓鞘形成的生物学理解。研究昼夜节律系统如何通过以下方式调节髓鞘形成： 1) 两种截然不同但又不同的神经细胞的发育靶向 OPC 中 Bmal1 敲低的互补遗传小鼠模型以探测发育性髓鞘形成 2) 环境时间破坏性慢性时差 (CJL) 模型在发育髓鞘形成中的应用，以及 3) 我们的初步数据证实，神经元活动引起的适应性髓鞘形成的昼夜变化会敲击遗传。在胚胎和产后发育过程中，OPCs 中 Bmal1 驱动的生物钟下降会导致 1) OPC 密度降低，2) OPC 增殖，3) 髓鞘形成，4) 髓磷脂相关行为 A。全面了解昼夜节律调节与 OPC 维护和髓鞘形成之间的相互作用不仅会提供有关大脑健康机制的信息，还会深入了解潜在的治疗策略针对多种脑部疾病中髓磷脂特异性昼夜节律调节过程。