Novel molecular mediators for activity-dependent myelination

活性依赖性髓鞘形成的新型分子介质

基本信息

  • 批准号:
    10521885
  • 负责人:
  • 金额:
    $ 37.89万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-06-01 至 2027-05-31
  • 项目状态:
    未结题

项目摘要

ABSTRACT The majority of axons in the central nervous system (CNS) are wrapped with compact layers of myelin sheaths to ensure the rapid transmission of neuronal signals over long distances. As myelin thickness and sheath length have profound effects on conduction velocity, myelination is also crucial to the precise control of spatiotemporal activity patterns in the CNS. In the mammalian spinal cord, both descending motor and ascending sensory pathways travel over long distances, requiring fine control of conduction speed necessary for sensory-motor integration. Myelin disruption in the spinal cord after CNS trauma or disease, like multiple sclerosis, causes axonal conduction failure leading to severe impairment of neurological function. Accumulating data support the notion that neuronal activity positively regulates myelin development and also induces adaptive myelin plasticity in adulthood. However, the underlying mechanisms are still not fully understood, and no molecular mediators have been identified regulating this process. Alpha2delta1 (A2d1) subunits of voltage-gated Ca2+ channels (VGCCs) positively regulate the plasma membrane expression and the biophysical properties of VGCCs, including those controlling synaptic vesicle release. Our preliminary data suggest that A2d1 subunits positively regulate myelin development in the murine spinal cord. Building on our promising data, the proposed study aims at dissecting the neuronal- and glial-specific mechanisms underlying the role of A2d1 subunits in myelin development and repair. We propose a series of gain- and loss-of-function experiments to investigate how A2d1 subunits expressed in neurons and oligodendrocyte precursor cells positively regulate myelin development. Additionally, we will test whether manipulating A2d1 subunits effectively promotes remyelination and functional recovery after demyelinating injury. Overall, this study will shed light on the molecular mechanisms underlying activity-dependent myelin formation and plasticity and contribute to the design of translational research aimed at restoring myelin and neurological function after CNS trauma and disease.
摘要 中枢神经系统(CNS)中的大多数轴突被致密的髓鞘包裹 以确保神经信号的长距离快速传输。作为髓鞘厚度和鞘 长度对传导速度有深刻的影响,髓鞘形成也是精确控制的关键 中枢神经系统的时空活动模式。在哺乳动物的脊髓中,下行运动和 上升的感官通路需要长距离传播,需要对传导速度进行必要的精细控制。 用于感觉和运动的整合。中枢神经系统损伤或疾病后脊髓髓鞘破坏,如多发性 硬化症,导致轴突传导衰竭,导致神经功能严重受损。 越来越多的数据支持神经元活动积极调节髓鞘发育的观点,而且 在成年期诱导适应性髓鞘可塑性。然而,潜在的机制仍然不完全 理解,而且还没有发现调节这一过程的分子介体。Alpha2delta1(A2d1) 电压门控钙通道亚单位(VGCC)正向调节质膜表达, VGCC的生物物理特性,包括那些控制突触小泡释放的特性。我们的初步数据 提示A2d1亚单位对小鼠脊髓髓鞘发育有积极的调节作用。建立在我们的 有前景的数据,这项拟议的研究旨在剖析神经元和神经胶质细胞特有的机制 A2d1亚基在髓鞘发育和修复中的作用。我们提出了一系列增益函数和损耗函数 A2d1亚单位在神经元和少突胶质前体细胞中表达的实验研究 积极调节髓鞘发育。此外,我们将测试是否操纵A2d1亚单位 有效促进脱髓鞘损伤后的再髓鞘形成和功能恢复。总体而言,这项研究将 阐明了依赖活性的髓鞘形成和可塑性的分子机制 参与旨在恢复CNS后髓鞘和神经功能的转译研究的设计 创伤和疾病。

项目成果

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Wenjing Sun其他文献

Wenjing Sun的其他文献

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{{ truncateString('Wenjing Sun', 18)}}的其他基金

Novel molecular mediators for activity-dependent myelination
活性依赖性髓鞘形成的新型分子介质
  • 批准号:
    10622530
  • 财政年份:
    2022
  • 资助金额:
    $ 37.89万
  • 项目类别:

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