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
基本信息
- 批准号:8354138
- 负责人:
- 金额:$ 242.93万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-09-30 至 2017-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAlzheimer&aposs DiseaseAmyotrophic Lateral SclerosisArchitectureBindingCell membraneCellsChronicComplexCuesDefectDevelopmentDrosophila genusEventExhibitsGrowthImageInterventionLeadLearningLifeLocationMembraneMembrane Protein TrafficMemoryModelingMolecularMorphologyNeurodegenerative DisordersNeuromuscular JunctionNeuronsProcessPropertyProteomicsReceptor SignalingRegulationRouteSignal TransductionStructureSynapsesSynaptic VesiclesSystemTestingWorkabstractingcell growth regulationin vivonervous system disorderpresynapticpublic health relevancereceptorreceptor internalizationresponsetrafficking
项目摘要
DESCRIPTION (Provided by the applicant)
Abstract: Neurons grow elaborate structures tailored to send and receive electrical signals over large distances and through complex networks of connections. Neuronal morphology in these networks changes dynamically in response to both neuronal firing and external growth cues, during development as well as learning and memory, and recedes in the absence of positive growth cues. These growth cues are transduced by receptors that exhibit subcellular location-dependent signaling properties as they are internalized from the plasma membrane and trafficked through endosomal compartments, and therefore regulation of membrane traffic can profoundly alter growth signaling. The intersection of signaling and membrane traffic is particularly intriguing in the presynaptic compartment of neurons, because synapses are highly specialized for both exocytic and endocytic traffic of synaptic vesicles in response to activity. Signaling receptor internalization and the synaptic vesicle cycle use a highly overlapping set of trafficking machinery, but little is understood about cross-talk between these processes and how activity-dependent modes of regulation of trafficking machinery might be used to control signal transduction. These membrane trafficking events are deeply implicated in neurodegenerative diseases, and understanding how they are regulated by neuron-specific mechanisms may lead to new routes for intervention. We are using the Drosophila larval neuromuscular junction (NMJ) to unravel the molecular mechanisms by which activity-dependent changes in receptor traffic lead to changes in synaptic growth signaling and synaptic architecture. This proposal combines two approaches to determining how receptor traffic in this system is regulated by activity: (1) live imaging of signaling receptor traffic and in response to chronic and acute changes in activity, and (2) proteomic analyses of activity-dependent changes in the membrane traffic machinery. We will then combine our findings about molecular mechanisms of activity-dependent regulation of endocytic traffic with in vivo tests of traffic of synaptic growth receptor, leading to models for how activity works through the membrane traffic machinery to tune signaling up or down for structural remodeling of neurons, and for how mis-regulation of these cellular trafficking events might contribute to neurodegenerative disease.
Public Health Relevance: Neurons undergo dynamic structural changes in response to external growth signals during development as well as learning and memory. Growth signals are trafficked into the cell via membrane-bound compartments, and defects in these events are a hallmark of neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) and Alzheimer's disease. We propose to investigate how neurons control the formation of membrane compartments and load them with specific signaling cargoes, and identify ways to manipulate these events to treat neurological disease.
描述(由申请人提供)
摘要:神经元生长出精心设计的结构,可以通过复杂的连接网络远距离发送和接收电信号。在这些网络中的神经元形态动态变化的神经元放电和外部的生长线索,在发展以及学习和记忆,并在没有积极的生长线索消退。这些生长信号由表现出亚细胞位置依赖性信号传导特性的受体转导,因为它们从质膜内化并通过内体隔室运输,因此膜运输的调节可以深刻地改变生长信号传导。信号传导和膜运输的交叉在神经元的突触前区室中是特别有趣的,因为突触高度专门化用于响应活动的突触囊泡的胞吐和胞吞运输。信号受体内化和突触囊泡周期使用一套高度重叠的贩运机制,但很少有人了解这些过程之间的串扰和如何依赖于活动的贩运机制的调节模式可能被用来控制信号转导。这些膜运输事件与神经退行性疾病密切相关,了解它们如何受到神经元特异性机制的调控可能会导致新的干预途径。 我们正在使用果蝇幼虫神经肌肉接头(NMJ)来阐明受体交通的活动依赖性变化导致突触生长信号传导和突触结构变化的分子机制。该提案结合了两种方法来确定该系统中的受体交通如何受活动调节:(1)信号受体交通的实时成像以及对活动的慢性和急性变化的响应,以及(2)膜交通机制中活动依赖性变化的蛋白质组学分析。然后,我们将结合我们的发现联合收割机的活动依赖性调节的内吞交通的分子机制与突触生长受体的交通在体内测试,导致模型的活动如何通过膜交通机制,以调整信号向上或向下的神经元结构重塑,以及如何错误调节这些细胞运输事件可能有助于神经退行性疾病。
公共卫生相关性:神经元在发育以及学习和记忆过程中响应外部生长信号而经历动态结构变化。生长信号通过膜结合区室被运输到细胞中,并且这些事件中的缺陷是神经退行性疾病如肌萎缩性侧索硬化症(ALS)和阿尔茨海默病的标志。我们建议研究神经元如何控制膜隔室的形成,并使其负载特定的信号货物,并确定操纵这些事件来治疗神经系统疾病的方法。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Tissue-specific tagging of endogenous loci in Drosophila melanogaster.
果蝇中内源性基因座的组织特异性标记。
- DOI:10.1242/bio.016089
- 发表时间:2015-12-23
- 期刊:
- 影响因子:2.4
- 作者:Koles K;Yeh AR;Rodal AA
- 通讯作者:Rodal AA
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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:
$ 242.93万 - 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:
$ 242.93万 - 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:
$ 242.93万 - 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:
$ 242.93万 - 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:
$ 242.93万 - 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:
$ 242.93万 - 项目类别:
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
- 批准号:
10584339 - 财政年份:2017
- 资助金额:
$ 242.93万 - 项目类别:
Structure and regulation of synaptic architecture
突触结构的结构和调节
- 批准号:
8118493 - 财政年份:2009
- 资助金额:
$ 242.93万 - 项目类别:
Structure and regulation of synaptic architecture
突触结构的结构和调节
- 批准号:
8311045 - 财政年份:2009
- 资助金额:
$ 242.93万 - 项目类别:
Structure and regulation of synaptic architecture
突触结构的结构和调节
- 批准号:
8142491 - 财政年份:2009
- 资助金额:
$ 242.93万 - 项目类别: