Neuropeptides as axonal determinants for oligodendrocyte differentiation and myelination
神经肽作为少突胶质细胞分化和髓鞘形成的轴突决定因素
基本信息
- 批准号:10308513
- 负责人:
- 金额:$ 39.93万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-12-01 至 2025-11-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdultAffectAxonBehaviorBindingBiologyCSPG4 geneCaliberCell Differentiation processCell LineageCell ProliferationCellsCharacteristicsCoculture TechniquesComplexCorpus striatum structureCre driverCuesDataDense Core VesicleDevelopmentDoseDynorphinsFRAP1 geneFiberG-Protein-Coupled ReceptorsGene ExpressionGene Expression ProfilingGenerationsGenetic RecombinationHistologicIn VitroInterneuronsKnockout MiceLabelMAP Kinase GeneMAPK3 geneMediatingMediator of activation proteinMembraneMinorMolecularMusMuscarinicsMyelinNeuronsNeuropeptidesOligodendrogliaOpioid agonistPathway interactionsPatternPeptidesPhenocopyPopulationPositioning AttributeProcessReceptor ActivationReporterSelective Estrogen Receptor ModulatorsSignal PathwaySignal TransductionStressSwimmingacute stressantagonistbasebiophysical propertiesdesigner receptors exclusively activated by designer drugsextracellularhigh throughput screeninginsightkappa opioid receptorsmyelinationneuronal cell bodyneuronal circuitryneurotransmissionnoveloligodendrocyte myelinationoligodendrocyte precursorp38 Mitogen Activated Protein Kinasepostnatalprecursor cellresponsesmall moleculetau Proteinsvesicular release
项目摘要
This proposal focuses on addressing one of the most fundamental questions regarding OL biology: What
axonal cues in the CNS microenvironment control OL differentiation and myelination? While it is still yet
unclear whether the spatial and temporal patterns of myelination are dependent on inductive or inhibitory cues
(or both), we know that exclusively axons – but not all axons – are myelinated by OLs in parallel with neuronal
circuit maturation. This suggests that axon-derived signals must be involved in coordinating this process. In
this proposal, we have identified a novel axon-derived peptide class, namely dynorphins that promote OL
differentiation and myelination. Neuropeptides, have several characteristics that make them an ideal axonal
signal to regulate myelination. They are stored in dense core vesicles and released only in response to high
levels of neuronal activity, a phenomenon that might signal a form of maturation that qualifies an axon for
myelination. Neuropeptides bind to G-protein coupled receptors and have slow-acting effects that may include
altering gene expression, providing a mechanism through which they might alter cellular fate. In this proposal
we will investigate: 1. Whether OLs and their precursors are influenced by the neuropeptide class, dynorphin,
2. Whether dynorphins are released in response to neuronal activity to regulate myelination and 3. Whether
dynorphins influence myelination globally or is restricted only to dynorphin expressing axons. Recent studies
demonstrate that biophysical properties of fiber diameter, inhibitory molecules and neuronal activity may all
affect OL precursor cell (OPC) proliferation, differentiation, and the selection of axons for myelination (Gibson
et al., 2014; Hines et al., 2015; Mensch et al., 2015; Redmond et al., 2016; Mitew et al., 2018; Mayoral et al.,
2018). Here, we provide the molecular mechanism and downstream signaling pathways for a specific
subset of neurons that may underlie activity dependent differentiation and myelination. Our preliminary
data place us in a unique position to determine whether dynorphins are a neuropeptide class that represents
an axonal cue to control OL differentiation and myelination. We believe that these findings should impart
valuable insight in providing a framework for identifying additional neuropeptides and transmitters that may
influence oligodendroglial lineage cells, as well as for profiling inhibitory and inductive cues for myelination.
该建议重点是解决有关OL生物学的最根本问题之一:什么
中枢神经系统微环境控制OL分化和髓鞘形成中的轴突提示?虽然还在
不清楚髓鞘化的空间和临时模式是否取决于感应或抑制性提示
(或两者兼而
电路成熟。这表明轴突衍生的信号必须参与此过程的协调。在
这项建议,我们确定了一种新型的轴突衍生的肽类,即促进OL的Dynorphins
分化和髓鞘。神经肽具有多种特征,使其成为理想的轴突
信号调节髓鞘。它们存储在密集的核心蔬菜中,仅是为了响应高
神经元活性的水平,这种现象可能标志着一种成熟形式,使轴突有资格
髓鞘。神经肽与G蛋白偶联受体结合,并具有缓慢的作用,可能包括
改变基因表达,提供一种可能改变细胞命运的机制。在此提案中
我们将调查:1。OLS及其前体是否受神经肽类的影响Dynorphin,Dynorphin,
2。是否释放出对神经元活性以调节髓鞘的释放和3。
驱指在全球范围内影响髓鞘形成,或仅限于表达轴突的驱体。最近的研究
证明纤维直径,抑制分子和神经元活性的生物物理特性可能全部
影响OL前体细胞(OPC)增殖,分化和髓鞘轴突的选择(Gibson
等,2014; Hines等人,2015年; Mensch等人,2015年; Redmond等人,2016年; Mitew等人,2018年;市长等人,
2018)。在这里,我们为特定的分子机理和下游信号通路提供
神经元的子集可能是活性依赖分化和髓鞘形成的基础。我们的初步
数据使我们处于独特的位置,以确定Dynoprhis是否是代表的神经肽类
轴突提示,以控制OL分化和髓鞘形成。我们相信这些发现应该传达
有价值的见解提供了一个框架来识别可能的其他神经肽和发射器
影响寡头谱系细胞,以及用于分析抑制性和髓鞘的感应线索。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jonah R Chan其他文献
Jonah R Chan的其他文献
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{{ truncateString('Jonah R Chan', 18)}}的其他基金
Cell-type, circuit and network mechanisms of adult oligodendrogenesis in memory storage and retrieval
成体少突胶质细胞发生在记忆存储和检索中的细胞类型、回路和网络机制
- 批准号:
10606616 - 财政年份:2021
- 资助金额:
$ 39.93万 - 项目类别:
Cell-type, circuit and network mechanisms of adult oligodendrogenesis in memory storage and retrieval
成体少突胶质细胞发生在记忆存储和检索中的细胞类型、回路和网络机制
- 批准号:
10443712 - 财政年份:2021
- 资助金额:
$ 39.93万 - 项目类别:
Neuropeptides as axonal determinants for oligodendrocyte differentiation and myelination
神经肽作为少突胶质细胞分化和髓鞘形成的轴突决定因素
- 批准号:
10132642 - 财政年份:2020
- 资助金额:
$ 39.93万 - 项目类别:
Neuropeptides as axonal determinants for oligodendrocyte differentiation and myelination
神经肽作为少突胶质细胞分化和髓鞘形成的轴突决定因素
- 批准号:
10526408 - 财政年份:2020
- 资助金额:
$ 39.93万 - 项目类别:
Functional Screening of GPCR Small Molecule Libraries for Remyelination Therapies
用于髓鞘再生治疗的 GPCR 小分子文库的功能筛选
- 批准号:
9984143 - 财政年份:2016
- 资助金额:
$ 39.93万 - 项目类别:
The establishment of Schwann cell polarity and the initiation of myelination
雪旺细胞极性的建立和髓鞘形成的启动
- 批准号:
8842206 - 财政年份:2008
- 资助金额:
$ 39.93万 - 项目类别:
THE ESTABLISHMENT OF SCHWANN CELL POLARITY AND THE INITIATION OF MYELINATION
雪旺细胞极性的建立和髓鞘形成的启动
- 批准号:
8136007 - 财政年份:2008
- 资助金额:
$ 39.93万 - 项目类别:
The establishment of Schwann cell polarity and the initiation of myelination
雪旺细胞极性的建立和髓鞘形成的启动
- 批准号:
8762139 - 财政年份:2008
- 资助金额:
$ 39.93万 - 项目类别:
THE ESTABLISHMENT OF SCHWANN CELL POLARITY AND THE INITIATION OF MYELINATION
雪旺细胞极性的建立和髓鞘形成的启动
- 批准号:
7506647 - 财政年份:2008
- 资助金额:
$ 39.93万 - 项目类别:
THE ESTABLISHMENT OF SCHWANN CELL POLARITY AND THE INITIATION OF MYELINATION
雪旺细胞极性的建立和髓鞘形成的启动
- 批准号:
8075921 - 财政年份:2008
- 资助金额:
$ 39.93万 - 项目类别:
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