Mechanisms of Developmental Myelination

发育性髓鞘形成机制

• 批准号: 10402866
• 负责人: Bruce H Appel
• 金额: $ 91.86万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2029-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10402866
• 关键词: Adult; Animals; Area; Axon; Biological Models; Brain; Brain Injuries; Cell Differentiation process; Cell Proliferation; Cells; Characteristics; Data; Development; Disease; Foundations; Genetic; Goals; Growth; Image; Immune; Injury; Investigation; Learning; Membrane; Memory; Mental disorders; Messenger RNA; Microglia; Molecular; Motor; Myelin; Myelin Sheath; Neuraxis; Neuroglia; Neurons; Oligodendroglia; Pharmacology; Proteolipids; Research; Specific qualifier value; Testing; Therapeutic; Time; Zebrafish; cell behavior; design; insight; myelination; nerve stem cell; oligodendrocyte precursor; precursor cell; programs; response; single-cell RNA sequencing

PROJECT SUMMARY The long-term goal of this research program is to understand how specific axons of the developing central nervous system (CNS) are ensheathed with specific amounts of myelin, a specialized, proteolipid-rich membrane produced by oligodendroglia. During development, subpopulations of neural progenitors produce oligodendrocyte precursor cells (OPCs), which migrate and divide to populate the CNS. Subsequently, some OPCs differentiate as myelinating oligodendrocytes whereas other OPCs persist through adulthood. Importantly, myelin is plastic and can be modified by brain activity. Recent evidence indicates that changes in OPC proliferation, oligodendrocyte differentiation, myelin sheath characteristics and axon selection for myelination contribute to myelin plasticity. However, the molecular mechanisms that regulate myelination, particularly in response to neuronal activity, are poorly understood. The investigations that comprise this research program focus on three broad areas of developmental myelination. First, using single cell RNA-seq data we generated, we will investigate how neural progenitors are specified as OPCs. Second, will axo-glial interactions and mRNA localization promote myelin sheath growth. Third, we will investigate how microglia, the resident innate immune cells of the CNS, modify myelin coverage on axons in response to neuronal activity. We use zebrafish as a model system, which enables us to combine time-lapse imaging with genetic and pharmacological manipulations to observe and test cell behaviors and myelination in an intact, living animal. The results of this research program have the potential to provide important new insights to the developmental basis of learning, memory and psychiatric disease and to provide a foundation for designing therapeutic strategies to promote myelination of brains damaged by disease or injury.

项目摘要 该研究计划的长期目标是了解发展中心的特定轴突如何 神经系统（CNS）带有特定量的髓磷脂，一种专门的，富含蛋白质的元素 少突胶质细胞产生的膜。在开发过程中，神经祖细胞的亚群会产生 少突胶质细胞前体细胞（OPC）迁移并分裂以填充CNS。随后，有些 OPC与髓鞘的少突胶质细胞不同，而其他OPC一直持续到成年。 重要的是，髓磷脂是塑性的，可以通过大脑活动来修饰。最近的证据表明 OPC增殖，少突胶质细胞分化，髓鞘特性和轴突选择 髓鞘形成有助于髓鞘可塑性。但是，调节髓鞘的分子机制， 特别是为了响应神经元活性，知之甚少。构成这一点的调查 研究计划的重点是发展性髓鞘的三个广泛领域。首先，使用单细胞RNA-seq 我们生成的数据，我们将研究如何将神经祖细胞指定为OPC。其次，将要轴向 相互作用和mRNA定位促进髓鞘的生长。第三，我们将研究小胶质细胞 中枢神经系统的居民先天免疫细胞可在神经元活性上修饰轴突上的髓磷脂覆盖率。 我们使用斑马鱼作为模型系统，使我们能够将延时成像与遗传和 在完整的活动物中观察和测试细胞行为和髓鞘的药理操作。 该研究计划的结果有潜力为发展提供重要的新见解 学习，记忆和精神病的基础，并为设计治疗提供基础 促进疾病或受伤受损大脑的髓鞘的策略。