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
- 来源:
- 关键词:Action PotentialsAdultAffinityAnatomyAxonBehavior assessmentBehavioralBindingBiochemicalCalcium ChannelCell Differentiation processCell ProliferationCell membraneCellsCervicalCoculture TechniquesDataDemyelinating DiseasesDemyelinationsDevelopmentDiseaseElectrophysiology (science)EnsureExhibitsFailureGenesHistologicImmunohistochemistryImpairmentIn VitroInjuryKnockout MiceLengthLightLysophosphatidylcholinesMammalsMediatingMediator of activation proteinModelingMolecularMolecular TargetMotorMultiple SclerosisMusMyelinMyelin ProteinsMyelin SheathNervous System PhysiologyNeuraxisNeurologicNeuronsOligodendrogliaPathway interactionsPatternPharmacologyPresynaptic TerminalsProcessProliferatingProteinsPublishingRecovery of FunctionRoleSensorySeriesSignal TransductionSpeedSpinal CordSynapsesSynaptic TransmissionSynaptic VesiclesTamoxifenTechniquesTestingTherapeuticTherapeutic InterventionThickTransgenic MiceTranslational ResearchTraumaTraumatic CNS injuryTravelbasebiophysical propertiescell behaviorcentral nervous system injuryconditional knockoutdesigndorsal columnexperimental studygabapentingenetic approachimaging approachin vivointerdisciplinary approachloss of functionmyelinationnervous system developmentneural networkneurotransmissionneurotransmitter releasenoveloligodendrocyte lineageoligodendrocyte precursoroverexpressionprecursor cellpresynapticpromoterremyelinationrepairedspatiotemporaltherapeutically effectivetranscriptomicstransmission processvesicular releaseviral gene deliveryvoltage
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.
抽象的
中枢神经系统 (CNS) 中的大部分轴突都包裹着致密的髓鞘层
确保神经元信号长距离快速传输。由于髓磷脂厚度和鞘
长度对传导速度有深远的影响,髓鞘形成对于精确控制也至关重要
中枢神经系统的时空活动模式。在哺乳动物脊髓中,下行运动和
上行感觉通路需要长距离传播,需要对传导速度进行精细控制
用于感觉运动整合。中枢神经系统创伤或疾病(如多发性硬化症)后脊髓中的髓磷脂破坏
硬化,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这样的观点:神经元活动积极调节髓磷脂的发育,并且
诱导成年期的适应性髓磷脂可塑性。但底层机制尚未完全完善
已被理解,并且尚未发现调节该过程的分子介质。阿尔法2德尔塔1 (A2d1)
电压门控 Ca2+ 通道 (VGCC) 亚基正向调节质膜表达和
VGCC 的生物物理特性,包括控制突触小泡释放的特性。我们的初步数据
表明 A2d1 亚基正向调节小鼠脊髓中的髓磷脂发育。建立在我们的
有希望的数据,拟议的研究旨在剖析潜在的神经元和胶质细胞特异性机制
A2d1 亚基在髓磷脂发育和修复中的作用。我们提出了一系列的功能获得和丧失
研究 A2d1 亚基如何在神经元和少突胶质细胞前体细胞中表达的实验
积极调节髓磷脂的发育。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。总体而言,本研究将
揭示了活性依赖性髓磷脂形成和可塑性的分子机制
有助于设计旨在恢复中枢神经系统术后髓磷脂和神经功能的转化研究
创伤和疾病。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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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