Synapse to Nuclear Signaling During Long-Lasting Neuronal Plasticity
持久神经元可塑性期间突触到核信号传导
基本信息
- 批准号:8848886
- 负责人:
- 金额:$ 37.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-07-05 至 2018-03-31
- 项目状态:已结题
- 来源:
- 关键词:Active Biological TransportAddressAffectAlzheimer&aposs DiseaseAwardBiologicalCREB1 geneCalciumCell NucleusCell physiologyCellsCellular biologyCognitionCognition DisordersCognitiveComplexCoupledCouplingCyclic AMPDendritesDiseaseDopamineEventFundingGene ExpressionGene Expression ProfileGene TargetingGenetic TranscriptionGlutamatesHealthHippocampus (Brain)HumanImportinsKnockout MiceLearningLifeLightLinkLong-Term PotentiationMass Spectrum AnalysisMediatingMemoryMemory DisordersMemory LossMental RetardationMicroscopyMusMutationNeuromodulatorNeuronal PlasticityNeuronsNorepinephrineNuclearNuclear ImportNuclear TranslocationPathway interactionsPatternPhosphorylationPost-Translational Protein ProcessingProcessProteinsProteomicsRNA SequencesReagentRecruitment ActivityRodentRoleSignal TransductionSignaling MoleculeSiteSmall Interfering RNAStimulusSynapsesSynaptic plasticitySystemTranscription CoactivatorTravelage relatedcellular imagingexcitatory neuronexperiencegene inductioninsightlenslong term memoryneuronal cell bodyneuropsychiatryneuroregulationnovelnucleocytoplasmic transportresearch studyresponseretrograde transporttraffickingtranscription factortranscriptome sequencing
项目摘要
DESCRIPTION (provided by applicant): Hebbian and homeostatic forms of synaptic plasticity require new gene expression for their persistence. For stimulus-induced alterations in transcription to occur, signals must be relayed from sites of synaptic stimulation to the nucleus. Such long-distance retrograde transport poses a unique set of challenges in neurons, where synapses can be located at great distances from the cell soma and nucleus. Electrochemical and calcium-dependent processes allow for extremely rapid signaling between subcellular compartments in neurons. Studies in a number of systems have also indicated that soluble signaling molecules can be transported from the synapse to the nucleus to effect changes in transcription. This proposal is aimed at elucidating the cell biology of synapse to nuclear signaling during long-lasting, learning-related synaptic plasticity in mouse hippocampal neurons. During the past funding cycle, we characterized a role for importin-mediated active nuclear import of synaptically localized transcription during hippocampal long-term potentiation. Synapse to nuclear transport of transcription factors provides a direct means of coupling synaptic activity with changes in gene expression. We focus this continuation proposal on the synapse to nuclear transport of the CREB regulated transcriptional coactivator CRTC1 during activity-dependent plasticity. We have shown that CRTC1 tracks glutamatergic activity in excitatory neurons to inform the nucleus about synaptic events. It is actively transported into the
nucleus from stimulated synapses, and undergoes profound changes in post-translational modification in response to stimulation. Moreover, while glutamatergic stimuli trigger CRTC1 nuclear import, neuromodulatory inputs that elevate intracellular cAMP regulate the persistence of CRTC1 in the nucleus. We have generated a number of reagents to study and manipulate CRTC1 in neurons and now propose to use these to perform an in-depth analysis of the cell biology and function of its synapse to nuclear signaling during long-term synaptic plasticity of mouse hippocampal neurons. Towards this end we propose three specific aims directed at answering three sets of questions: 1) How does CRTC1 travel from synapse to nucleus; 2) How does CRTC1 nuclear import alter gene expression? How do stimulus-induced change in CRTC1 phosphorylation alter its nuclear transport and downstream transcription? and 3) How does neuromodulation regulate CRTC1-mediated gene expression? The answers to these questions will provide insight into the cell biology of learning-related gene expression, and into the particular function of CRTC1. The results of our studies are relevant to a spectrum of neuropsychiatric disorders, and to cognitive disorders (such as mental retardation, Alzheimer's Disease and age-related memory loss) in which long-term memory is impaired.
描述(由申请人提供):Hebbian和稳态的突触可塑性形式需要新的基因表达才能使其持久性。为了刺激引起的转录发生变化,必须将信号从突触刺激部位传递到细胞核。这种长距离逆行转运在神经元中构成了一套独特的挑战,在该神经元中,突触可以位于距细胞体和核的距离很远的地方。电化学和钙依赖性过程允许神经元中亚细胞隔室之间的信号传导极快。在许多系统中的研究还表明,可溶性信号分子可以从突触传输到核以影响转录的变化。该建议旨在阐明在小鼠海马神经元中长期持久的,与学习相关的突触可塑性期间突触到核信号传导的细胞生物学。在过去的资金周期中,我们表征了进口素介导的在海马长期增强期间突触局部转录的活性核进口的作用。转录因子的核转运突触提供了与基因表达变化的偶联突触活动的直接手段。我们将这一延续建议集中在活动依赖性可塑性期间CREB调节的转录共激活因子CRTC1的突触。我们已经表明,CRTC1跟踪兴奋性神经元中的谷氨酸能活性,以告知细胞核突触事件。它被积极运输到
刺激突触的细胞核,并对刺激的反应后经历了翻译后修饰的深刻变化。此外,尽管谷氨酸能刺激会触发CRTC1核进口,但升高细胞内cAMP的神经调节输入调节了细胞核中CRTC1的持久性。我们已经生成了许多试剂来研究和操纵神经元中的CRTC1,现在建议使用这些试剂对小鼠海马神经元的长期突触可行性期间对细胞生物学的深入分析以及其突触与核信号的功能进行深入分析。为此,我们提出了三个旨在回答三组问题的特定目标:1)CRTC1如何从突触到核传播; 2)CRTC1核进口如何改变基因表达?刺激引起的CRTC1磷酸化变化如何改变其核转运和下游转录? 3)神经调节如何调节CRTC1介导的基因表达?这些问题的答案将洞悉与学习相关的基因表达的细胞生物学以及CRTC1的特定功能。我们的研究结果与一系列神经精神疾病有关,与认知障碍(例如智力低下,阿尔茨海默氏病和与年龄相关的记忆丧失)有关,其中长期记忆会受到损害。
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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Kelsey C Martin其他文献
Kelsey C Martin的其他文献
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{{ truncateString('Kelsey C Martin', 18)}}的其他基金
Cytoplasmic Functions of Rbfox1, a Candidate Autism Gene
自闭症候选基因 Rbfox1 的细胞质功能
- 批准号:
8572004 - 财政年份:2013
- 资助金额:
$ 37.68万 - 项目类别:
Cytoplasmic Functions of Rbfox1, a Candidate Autism Gene
自闭症候选基因 Rbfox1 的细胞质功能
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8695492 - 财政年份:2013
- 资助金额:
$ 37.68万 - 项目类别:
Importin-mediated signaling from synapse to nucleus during neuronal plasticity
神经元可塑性过程中输入蛋白介导的从突触到细胞核的信号传导
- 批准号:
7617010 - 财政年份:2007
- 资助金额:
$ 37.68万 - 项目类别:
Importin-mediated signaling from synapse to nucleus during neuronal plasticity
神经元可塑性过程中输入蛋白介导的从突触到细胞核的信号传导
- 批准号:
7802314 - 财政年份:2007
- 资助金额:
$ 37.68万 - 项目类别:
Developing RNA Interference for Gene Specific Silencing in Aplysia Neurons
开发用于海兔神经元基因特异性沉默的 RNA 干扰
- 批准号:
7392756 - 财政年份:2007
- 资助金额:
$ 37.68万 - 项目类别:
Importin-mediated signaling from synapse to nucleus during neuronal plasticity
神经元可塑性过程中输入蛋白介导的从突触到细胞核的信号传导
- 批准号:
8066434 - 财政年份:2007
- 资助金额:
$ 37.68万 - 项目类别:
Developing RNA Interference for Gene Specific Silencing in Aplysia Neurons
开发用于海兔神经元基因特异性沉默的 RNA 干扰
- 批准号:
7256565 - 财政年份:2007
- 资助金额:
$ 37.68万 - 项目类别:
Importin-mediated signaling from synapse to nucleus during neuronal plasticity
神经元可塑性过程中输入蛋白介导的从突触到细胞核的信号传导
- 批准号:
7317570 - 财政年份:2007
- 资助金额:
$ 37.68万 - 项目类别:
Synapse to Nuclear Signaling During Long-Lasting Neuronal Plasticity
持久神经元可塑性期间突触到核信号传导
- 批准号:
8697297 - 财政年份:2006
- 资助金额:
$ 37.68万 - 项目类别:
The Ubiquitin Proteasome Pathway & Synaptic Plasticity
泛素蛋白酶体途径
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6707163 - 财政年份:2003
- 资助金额:
$ 37.68万 - 项目类别:
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