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：
Avital Adah Rodal
金额：
$ 242.93万
依托单位：
BRANDEIS UNIVERSITY
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

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，可通过复杂的连接网络远距离发送和接收电信号。这些网络中的神经元形态在发育以及学习和记忆过程中响应神经元放电和外部生长线索而动态变化，并在缺乏积极生长线索的情况下消退。这些生长信号由受体转导，这些受体表现出亚细胞位置依赖性信号传导特性，因为它们从质膜内化并通过内体区室运输，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点在神经元的突触前区室中特别令人感兴趣，因为突触对于响应活动的突触小泡的胞吐和内吞运输高度专业化。信号受体内化和突触小泡循环使用一组高度重叠的运输机制，但人们对这些过程之间的串扰以及如何使用运输机制的活动依赖性调节模式来控制信号转导知之甚少。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节可能会带来新的干预途径。我们正在利用果蝇幼虫神经肌肉接头（NMJ）来揭示受体交通活动依赖性变化导致突触生长信号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流量如何受活性调节：（1）信号受体流量的实时成像以及对活性的慢性和急性变化的响应，以及（2）对活性依赖性变化的蛋白质组分析膜交通机械。然后，我们将把我们关于内吞交通活动依赖性调节的分子机制的发现与突触生长受体交通的体内测试相结合，从而建立活动如何通过膜交通机制来调节信号传导以进行结构重塑的模型。神经元，以及这些细胞运输事件的错误调节如何可能导致神经退行性疾病。公共健康相关性：神经元在发育以及学习和记忆过程中会经历动态结构变化，以响应外部生长信号。生长信号通过膜结合区室输送到细胞中，这些事件中的缺陷是肌萎缩侧索硬化症 (ALS) 和阿尔茨海默病等神经退行性疾病的标志。我们建议研究神经元如何控制膜室的形成并向其加载特定的信号传导货物，并确定操纵这些事件以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）

Coordinated autoinhibition of F-BAR domain membrane binding and WASp activation by Nervous Wreck.

Nervous Wreck 协调 F-BAR 结构域膜结合和 WASp 激活的自抑制。

DOI：
发表时间：
2016-09-20
期刊：
影响因子：
11.1
作者：
Stanishneva;Kelley, Charlotte F;Eskin, Tania L;Messelaar, Emily M;Wasserman, Steven A;Sokolova, Olga S;Rodal, Avital A
通讯作者：
Rodal, Avital A

Tissue-specific tagging of endogenous loci in Drosophila melanogaster.

果蝇内源基因座的组织特异性标记。