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层包裹 以确保神经元信号的长距离快速传输。由于髓鞘厚度和鞘 长度对传导速度有深远的影响,髓鞘形成对精确控制神经传导速度也至关重要。 CNS的时空活动模式。在哺乳动物的脊髓中,下行运动和 上行的感觉通路要走很长的距离,需要精细控制传导速度 用于感觉运动整合。中枢神经系统创伤或疾病后脊髓中的髓鞘破坏,如多发性骨髓瘤。 硬化,引起轴突传导失败,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, 在成年期诱导适应性髓鞘可塑性。然而,其内在机制仍然不完全 理解,并没有分子介质已确定调节这一进程。α 2 δ 1(A2d1) 电压门控钙通道亚基(VGCC)正调控质膜表达, VGCC的生物物理特性,包括控制突触囊泡释放的特性。我们的初步数据 提示A2d1亚单位正调控鼠脊髓中髓鞘的发育。充分发挥两国 有希望的数据,拟议的研究旨在解剖神经元和神经胶质细胞的具体机制, A2d1亚基在髓鞘发育和修复中的作用。我们提出了一系列的增益和损失的功能 研究A2d1亚基如何在神经元和少突胶质前体细胞中表达的实验 积极调节髓鞘发育。此外,我们将测试是否操纵A2d1亚基 有效促进脱髓鞘损伤后的髓鞘再生和功能恢复。总的来说,这项研究将 阐明了活动依赖性髓鞘形成和可塑性的分子机制, 有助于设计旨在恢复CNS后髓鞘和神经功能的转化研究 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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