The role of a novel viral-like signalling pathway in synaptic plasticity and neurological disorders
新型病毒样信号通路在突触可塑性和神经系统疾病中的作用
基本信息
- 批准号:10430205
- 负责人:
- 金额:$ 36.64万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-15 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:3&apos Untranslated RegionsActinsAddressAmino Acid SequenceAntibodiesBehaviorBindingBiological ModelsCapsidCellsCo-ImmunoprecipitationsCommunicationCytoskeletonDegenerative DisorderDevelopmentDown-RegulationDrosophila genusEncapsulatedEpilepsyExhibitsGenesGeneticGenomeGoalsGrantHomologous GeneHumanInfectious AgentLearningMammalsMediatingMemoryMessenger RNAMolecularMultivesicular BodyMuscleNervous system structureNeuromuscular DiseasesNeuromuscular JunctionNeuronal PlasticityNeuronsPathway interactionsPhysiologicalPlayPresynaptic TerminalsProteinsRNARNA InterferenceRNA immunoprecipitation sequencingReagentReportingResearchReticulumRetrotransposonRoleSchizophreniaSelfish GenesSignal PathwaySignal TransductionSpinocerebellar AtaxiasSynapsesSynaptic VesiclesSynaptic plasticitySystemTestingTranscriptTransfer RNATravelUncertaintyUrsidae FamilyViralViral GenomeVirusWNT Signaling PathwayWorkexperimental studyextracellular vesiclesflygag Gene Productshuman diseaseintercellular communicationknock-downnervous system disorderneuromuscularneuron developmentneurotransmissionnovelparticlepostsynapticpresynapticprotein functiontraffickingviral RNA
项目摘要
We have discovered a novel viral-like signaling pathway associated with extracellular vesicles (EV). We
found the Drosophila homolog of ARC (Actin-Regulated Cytoskeleton-associated protein) (darc1), is
present in EVs as both an mRNA and protein. ARC is a master regulator of synaptic plasticity in the nervous
system of mammals and is crucial for learning and memory. dArc1 bears a domain resembling
retroviral/retrotransposon Gag-like proteins that multimerizes into a capsid that packages viral RNA. Our
work shows dARC1 forms a capsid, associates with its own RNA, and then transports the darc1 transcript
across the synapse. The transfer of dArc1 is needed for activity-dependent plasticity at the fly
neuromuscular junction (NMJ). Besides dArc1, it is unknown whether other genes are in this viral-like
pathway. We address this uncertainty in Aim 1. Here we describe our plan to identify other Gag-like
proteins in EVs, and we have already found another Gag protein enriched in EVs, that is encoded by the
retrotransposon Copia. We have found that Copia transfers across the synaptic bouton. When copia is
knocked down at the NMJ this strikingly leads to increased plasticity. This is the opposite of darc1, where
we reported a decrease in plasticity. In Aim 2 we focus on what cargoes are co-transferring with dArc1 and
Copia. We have identified through co-immunoprecipitation, mRNAs and proteins that associate with dArc1
and Copia. As to how the transfer of Arc occurs, we have found that the dArc1 3’untranslated region (UTR)
is necessary and sufficient for the transfer of dArc1 across synaptic boutons. We are now testing if the
dArc1 3’UTR directs the loading of dArc1 into EVs. As well, we propose experiments to understand how
darc1 and copia mediate synaptic plasticity. We have co-immunoprecipitated dArc1 and Copia to identify
potential interactors, and we will take a candidate approach to find genetic interactors. In preliminary work
we found that dArc1 is needed for proper WNT pathway signaling at the NMJ. Additionally, we observe
that Copia and dArc1 bind to some of the same proteins and mRNAs, suggesting that they may be
antagonistic to each other, thus potentially explaining their seemingly opposite roles in mediating plasticity.
Through this grant we will expand our understanding of EV trafficking and synaptic plasticity, while
describing a novel physiological function of a retrotransposon in neuronal communication.
我们发现了一种新的病毒样信号通路与细胞外囊泡(EV)。我们
发现了果蝇ARC(肌动蛋白调节的细胞凋亡相关蛋白)(darc 1)的同源物,
存在于EV中的mRNA和蛋白质。ARC是神经系统中突触可塑性的主要调节器,
哺乳动物的神经系统,对学习和记忆至关重要。dArc 1具有类似于
逆转录病毒/逆转录转座子GAG样蛋白,其多聚化成包装病毒RNA的衣壳。我们
研究表明,dARC 1形成衣壳,与自己的RNA结合,然后运输darc 1转录本
穿过突触dArc 1的转移是在飞行中依赖于活动的可塑性所必需的
神经肌肉接头(NMJ)。除了dArc 1,还不知道是否有其他基因在这种病毒样
通路我们在目标1中解决了这种不确定性。在这里,我们描述了我们的计划,以确定其他类似加格
我们已经发现了另一种在EV中富集的Gag蛋白,它是由
反转录转座子Copia。我们已经发现Copia在突触终扣上传递。当copia是
在NMJ处被击倒,这显著地导致了可塑性的增加。这与darc 1相反,
我们报告了可塑性的下降。在目标2中,我们关注哪些货物与dArc 1共同转移,
科皮亚我们已经通过免疫共沉淀鉴定了与dArc 1相关的mRNA和蛋白质,
和Copia。至于Arc的转移是如何发生的,我们发现dArc 1 3 '非翻译区(UTR)
是dArc 1跨突触终扣传递的必要和充分条件。我们现在正在测试,
dArc 1 3 'UTR指导dArc 1加载到EV中。同时,我们提出实验来了解如何
darc 1和copia介导突触可塑性。我们共免疫沉淀dArc 1和Copia,
潜在的相互作用者,我们将采取候选方法来寻找遗传相互作用者。在初步工作中
我们发现dArc 1是NMJ上适当的WNT通路信号传导所必需的。此外,我们观察到
Copia和dArc 1与一些相同的蛋白质和mRNA结合,这表明它们可能是
相互对立,从而潜在地解释了它们在调节可塑性方面似乎相反的作用。
通过这项资助,我们将扩大我们对EV运输和突触可塑性的理解,
描述了反转录转座子在神经元通讯中的新的生理功能。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Travis Thomson其他文献
Travis Thomson的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Travis Thomson', 18)}}的其他基金
The Role of a Novel Viral-Like Signaling Pathway in Synaptic Plasticity and Neurological Disorders
新型病毒样信号通路在突触可塑性和神经系统疾病中的作用
- 批准号:
10640952 - 财政年份:2019
- 资助金额:
$ 36.64万 - 项目类别:
The role of a novel viral-like signalling pathway in synaptic plasticity and neurological disorders
新型病毒样信号通路在突触可塑性和神经系统疾病中的作用
- 批准号:
10187668 - 财政年份:2019
- 资助金额:
$ 36.64万 - 项目类别:
The role of a novel viral-like signalling pathway in synaptic plasticity and neurological disorders
新型病毒样信号通路在突触可塑性和神经系统疾病中的作用
- 批准号:
9802983 - 财政年份:2019
- 资助金额:
$ 36.64万 - 项目类别:
相似海外基金
Impact of alternative polyadenylation of 3'-untranslated regions in the PI3K/AKT cascade on microRNA
PI3K/AKT 级联中 3-非翻译区的替代多聚腺苷酸化对 microRNA 的影响
- 批准号:
573541-2022 - 财政年份:2022
- 资助金额:
$ 36.64万 - 项目类别:
University Undergraduate Student Research Awards
How do untranslated regions of cannabinoid receptor type 1 mRNA determine receptor subcellular localisation and function?
1 型大麻素受体 mRNA 的非翻译区如何决定受体亚细胞定位和功能?
- 批准号:
2744317 - 财政年份:2022
- 资助金额:
$ 36.64万 - 项目类别:
Studentship
MICA:Synthetic untranslated regions for direct delivery of therapeutic mRNAs
MICA:用于直接递送治疗性 mRNA 的合成非翻译区
- 批准号:
MR/V010948/1 - 财政年份:2021
- 资助金额:
$ 36.64万 - 项目类别:
Research Grant
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10019570 - 财政年份:2019
- 资助金额:
$ 36.64万 - 项目类别:
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10223370 - 财政年份:2019
- 资助金额:
$ 36.64万 - 项目类别:
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10455108 - 财政年份:2019
- 资助金额:
$ 36.64万 - 项目类别:
Synergistic microRNA-binding sites, and 3' untranslated regions: a dialogue of silence
协同的 microRNA 结合位点和 3 非翻译区:沉默的对话
- 批准号:
255762 - 财政年份:2012
- 资助金额:
$ 36.64万 - 项目类别:
Operating Grants
Analysis of long untranslated regions in Nipah virus genome
尼帕病毒基因组长非翻译区分析
- 批准号:
20790351 - 财政年份:2008
- 资助金额:
$ 36.64万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
Search for mRNA elements involved in the compatibility between 5' untranslated regions and coding regions in chloroplast translation
寻找参与叶绿体翻译中 5 非翻译区和编码区之间兼容性的 mRNA 元件
- 批准号:
19370021 - 财政年份:2007
- 资助金额:
$ 36.64万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Post-transcriptional Regulation of PPAR-g Expression by 5'-Untranslated Regions
5-非翻译区对 PPAR-g 表达的转录后调控
- 批准号:
7131841 - 财政年份:2006
- 资助金额:
$ 36.64万 - 项目类别: