Signaling Pathways that Regulate Synaptic Transmission

调节突触传递的信号通路

基本信息

批准号：
8641383
负责人：
KENNETH George MILLER
金额：
$ 34.86万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-08-17 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8641383
关键词：
Affect Affinity Chromatography Animal Model Animals Appearance Automobile Driving Axon Behavior Behavioral Biochemical Biochemistry Biological Biological Assay Brain Caenorhabditis elegans Candidate Disease Gene Cells Chimeric Proteins Complex Data Dense Core Vesicle Gases Genes Genetic Genetic Screening Human Image Imaging Techniques Knowledge Learning Life Locomotion Mediating Membrane Protein Traffic Memory Memory Disorders Mental Depression Methods Movement Nature Nervous system structure Neurons Neuropeptides Organism Pathway interactions Perception Phenotype Play Proteins Relative (related person)Resolution Role Schizophrenia Shapes Signal Pathway Signal Transduction Sleep Sleep Disorders Synapses Synaptic Transmission Testing Thinking Transistors driving behavior genetic analysis head involution defective protein in vivo insight mutant nervous system disorder neuronal cell body novel research study response time use tool trafficking

项目摘要

DESCRIPTION (provided by applicant): Our brains are packed with trillions of biological transistors known as synapses, which control the flow of information that produces our movements, perceptions, thoughts, and memories. To maintain order and plasticity within this vast interconnected network, neurons must have the ability to turn ON or OFF selected synapses. This project uses the genetic strengths of the model organism C. elegans to investigate the underlying signaling pathways and membrane trafficking mechanisms that allow neurons to regulate signaling across synapses. The pathways of a Ga signaling network control synaptic activity to produce the C. elegans locomotion behavior. These pathways are conserved in all neurons in all animals; however, how they control synaptic activity is not yet understood. This knowledge gap impedes progress in understanding the fundamental mechanisms that drive behavior and human brain functions ranging from sleep to complex thoughts and memories. A guiding hypothesis of this proposal, shaped by new preliminary data, is that the Ga pathways exert their major effects through Dense Core Vesicle (DCV) functions, and that there are important differences in how the pathways regulate DCVs in neuronal cell somas versus axons. Aim 1 of this proposal will use high resolution imaging techniques in living animals to investigate the relative contributions and interactions of the Gaq and Gas pathways in driving neuropeptide release from both cell somas and axons. We will also investigate the broad hypothesis, suggested by our recent studies of DCV maturation, that there is a DCV function unrelated to neuropeptides that is lost when the DCV maturation pathway malfunctions. By defining the maturation pathway in Aims 2 and 3 we hope to obtain clues about this missing function and bring a comprehensive model organism strategy to this under-investigated branch of membrane trafficking. We recently completed a genetic screen in C. elegans for DCV maturation mutants. The screen identified three proteins that, along with UNC-108 (Rab2), are core components in the DCV maturation pathway. These proteins, two of which have undefined functions, are conserved in all organisms with a nervous system, thus highlighting both the fundamental importance and novelty of this pathway. Aim 3 will combine a biochemical approach with a novel genetic approach to add further mechanistic insights to this new pathway. By combining the in vivo relevance of genetics, live animal imaging, and behavioral strategies with the mechanistic relevance of biochemistry, this project has the potential to transform intriguing preliminary findings into fundamental new insights that will begin bridging the gaps between the Ga signaling network, dense core vesicle functions, and behaviors.

描述（由申请人提供）：我们的大脑充满了数万亿个被称为突触的生物晶体管，它们控制着产生我们的运动、感知、思想和记忆的信息流。为了维持这个巨大的互连网络的秩序和可塑性，神经元必须能够打开或关闭选定的突触。该项目利用模式生物秀丽隐杆线虫的遗传优势来研究潜在的信号传导途径和膜运输机制，使神经元能够调节突触之间的信号传导。 Ga 信号网络的通路控制突触活动以产生线虫的运动行为。这些通路在所有动物的所有神经元中都是保守的；然而，它们如何控制突触活动尚不清楚。这种知识差距阻碍了对驱动行为和人类大脑功能（从睡眠到复杂的思想和记忆）的基本机制的理解。该提案的一个指导性假设是由新的初步数据形成的，即 Ga 途径通过致密核心囊泡 (DCV) 功能发挥其主要作用，并且这些途径在神经元细胞胞体和轴突中调节 DCV 的方式存在重要差异。该提案的目标 1 将使用高分辨率成像技术对活体动物进行研究 Gaq 和 Gas 途径在驱动细胞体和轴突释放神经肽方面的相对贡献和相互作用。我们还将研究我们最近对 DCV 成熟的研究所提出的广泛假设，即存在与神经肽无关的 DCV 功能，当 DCV 成熟途径发生故障时，该功能就会丢失。通过定义目标 2 和目标 3 中的成熟途径，我们希望获得有关这种缺失功能的线索，并为这一尚未充分研究的膜运输分支带来全面的模式生物策略。我们最近完成了对秀丽隐杆线虫 DCV 成熟突变体的遗传筛选。筛选确定了三种蛋白质，它们与 UNC-108 (Rab2) 一起是 DCV 成熟途径的核心成分。这些蛋白质（其中两种具有未定义的功能）在所有具有神经系统的生物体中都是保守的，从而突出了该途径的根本重要性和新颖性。目标 3 将生物化学方法与新颖的遗传方法相结合，为这一新途径添加进一步的机制见解。通过将遗传学、活体动物成像和行为策略的体内相关性与生物化学的机械相关性相结合，该项目有可能将有趣的初步发现转化为基本的新见解，从而开始弥合 Ga 信号网络、密集信号网络之间的差距。核心囊泡功能和行为。