Roles of Recycling Endosomes in Neuronal Extracellular Vesicle Cargo Traffic
回收内体在神经元细胞外囊泡货物运输中的作用
基本信息
- 批准号:10584339
- 负责人:
- 金额:$ 47.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-12-01 至 2027-11-30
- 项目状态:未结题
- 来源:
- 关键词:AcuteAlzheimer&aposs DiseaseBehaviorBindingBiochemistryBiogenesisBrainCarrier ProteinsCell membraneCellsCellular MembraneChemicalsClathrinCommunicationComplexDataDefectDiseaseDrosophila genusEndocytosisEndosomesEventFoundationsGeneticGoalsHumanKnowledgeLinkLipidsMediatingMembraneMembrane Protein TrafficMicroscopyMonitorMorphogenesisMorphologyNatureNerveNervous SystemNervous System PhysiologyNeurodegenerative DisordersNeurogliaNeuronsNucleic AcidsParkinson DiseasePathologicPathologyPathway interactionsPhosphotransferasesPhysiologicalPlasmaPlayPopulationPresynaptic TerminalsProcessProteinsReceptor SignalingRecyclingRegulationResearchResolutionRoleRouteSYNJ1 geneSignal TransductionSortingSynapsesSynaptic MembranesSynaptic TransmissionTestingTherapeuticVesicleWorkcell typeexperimental studyextracellular vesiclesgenetic approachimaging approachin vivoinsightintercellular communicationlive cell imagingmutantnervous system disordernoveloptogeneticspresynapticrab11 proteinresponseretrograde transportscaffoldtooltraffickingvesicular release
项目摘要
PROJECT SUMMARY
The goal of this proposal is to understand how cellular membrane trafficking machinery controls the packaging
and release of extracellular vesicle (EV) cargoes from synapses in vivo. EVs are small membrane-bound
vesicles released by numerous cell types, including neurons, carrying cargoes critical for signaling and
disease. However, we understand very little about how EV cargo traffic is spatially and temporally regulated
within the polarized and complex morphology of neurons. We have developed tools to track and manipulate EV
traffic at Drosophila presynaptic terminals in vivo, and discovered that flux of cargoes through a plasma
membrane-recycling endosome route determines whether they are locally sorted for packaging and release in
EVs, rather than depleted from synapses by retrograde transport. Recycling endosomes have primarily been
studied in non-neuronal cells, and very little is known about their lifetime, functions, or dynamics at presynaptic
terminals. We do know that recycling endosomes play critical roles in signaling, neuronal morphogenesis, EV
traffic, and synaptic transmission. Understanding and therapeutically intervening in these important processes
will require a deeper knowledge of the mechanisms of neuronal recycling endosome function. In this proposal,
we will elucidate the mechanisms of synaptic EV cargo and recycling endosome traffic in vivo. To achieve
these goals, we will use Drosophila genetics, biochemistry, high-resolution microscopy, and live cell imaging.
1) We will determine the functions, dynamics, and regulation of different types of synaptic recycling
endosomes. To this end, we will develop new tools and approaches to define and control functionally distinct
recycling compartments at synapses. Using these tools, we will test novel mechanistic hypotheses for how
membrane traffic machinery sorts cargoes at synaptic recycling compartments. 2) We will determine how EV
cargo traffic depends on distinct modes of synaptic endocytosis: clathrin-mediated endocytosis, which operates
under low neuronal activity and activity-dependent bulk endocytosis, which operates during intense neuronal
activity. These experiments will ascertain if EV fate is determined by different modes of internalization, how
recycling endosomes contribute to these functions, and provide new mechanisms to link activity, endosomal
traffic, and EV release. Given the conserved nature of synaptic membrane trafficking machinery, our findings
and tools will lay the foundation for new insights into EV traffic in many aspects of nervous system function,
including in human neurological disease.
项目摘要
这项建议的目的是了解细胞膜运输机械如何控制包装
以及在体内从突触释放细胞外囊泡(EV)货物。EV是小的膜结合的
由包括神经元在内的多种细胞类型释放的囊泡,携带对信号传导至关重要的货物,
疾病然而,我们对电动汽车货物运输在空间和时间上是如何调节的知之甚少
在极化和复杂的神经元形态中。我们已经开发了跟踪和操纵电动汽车的工具,
交通在果蝇突触前末梢在体内,并发现流量的货物通过血浆
膜再循环内体途径决定了它们是否被局部分选用于包装和释放,
而不是通过逆行运输从突触中耗尽。回收内体主要是
在非神经元细胞中进行了研究,并且对它们的寿命,功能或突触前动力学知之甚少
terminals.我们知道,内体循环在信号传导、神经元形态发生、EV
交通和突触传递。了解和治疗干预这些重要的过程
将需要更深入地了解神经元再循环内体功能的机制。在这项提案中,
我们将阐明突触EV货物和再循环内体运输在体内的机制。实现
为了实现这些目标,我们将使用果蝇遗传学、生物化学、高分辨率显微镜和活细胞成像技术。
1)我们将确定不同类型的突触再循环的功能、动力学和调节
核内体为此,我们将开发新的工具和方法来定义和控制功能上不同的
在突触处回收隔间。使用这些工具,我们将测试新的机制假设,
膜运输机械在突触回收隔间中分类货物。2)我们将确定EV
货物运输依赖于突触内吞作用的不同模式:网格蛋白介导的内吞作用,
在低神经元活性和活性依赖性大量内吞作用下,
活动这些实验将确定EV的命运是否由不同的内化模式决定,
内体再循环有助于这些功能,并提供了新的机制来连接活性,内体
交通和EV释放。鉴于突触膜运输机制的保守性,我们的发现
和工具将为在神经系统功能的许多方面对电动汽车交通的新见解奠定基础,
包括人类神经系统疾病。
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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Avital Adah Rodal其他文献
Avital Adah Rodal的其他文献
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{{ truncateString('Avital Adah Rodal', 18)}}的其他基金
Diversity Supplement (Monica Quinones-Frias): Roles of Recycling Endosomes in Neuronal Extracellular Vesicle Cargo Traffic
多样性补充剂(Monica Quinones-Frias):回收内体在神经元细胞外囊泡货物运输中的作用
- 批准号:
10782371 - 财政年份:2023
- 资助金额:
$ 47.48万 - 项目类别:
Abberior 3D-STED microscope for super-resolution imaging
用于超分辨率成像的 Abberior 3D-STED 显微镜
- 批准号:
10630881 - 财政年份:2023
- 资助金额:
$ 47.48万 - 项目类别:
Organization and Function of the Periactive Zone
周围活动区的组织和功能
- 批准号:
10600083 - 财政年份:2020
- 资助金额:
$ 47.48万 - 项目类别:
Organization and function of the periactive zone
周围活动区的组织和功能
- 批准号:
10381522 - 财政年份:2020
- 资助金额:
$ 47.48万 - 项目类别:
Mechanisms and regulation of extracellular vesicle traffic in the nervous system
神经系统细胞外囊泡运输的机制和调节
- 批准号:
10063578 - 财政年份:2017
- 资助金额:
$ 47.48万 - 项目类别:
Mechanisms and regulation of extracellular vesicle traffic in the nervous system
神经系统细胞外囊泡运输的机制和调节
- 批准号:
10308698 - 财政年份:2017
- 资助金额:
$ 47.48万 - 项目类别:
Activity-dependent regulation of membrane traffic and growth signaling in neurons
神经元膜交通和生长信号的活动依赖性调节
- 批准号:
8354138 - 财政年份:2012
- 资助金额:
$ 47.48万 - 项目类别: