Signaling Pathways that Regulate Synaptic Transmission

调节突触传递的信号通路

基本信息

批准号：
7777357
负责人：
KENNETH George MILLER
金额：
$ 32.27万
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 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7777357
关键词：
Address Affect Animal Model Animals Behavior Behavior Control Behavioral Behavioral Assay Caenorhabditis elegans Cholinergic Receptors Conflict (Psychology)Data Dense Core Vesicle Disease Dissection Drug Delivery Systems Funding Gases Genes Genetic Genetic Screening Goals Human Hyperactive behavior Image Imaging technology Learning Life Light Link Locomotion Logic Maps Mediating Membrane Memory Memory Disorders Mental Depression Mental disorders Modeling Molecular Molecular Target Muscle Mutate Mutation Neurons Paralysed Pathway Analysis Pathway interactions Process Proteins Regulation Research Research Personnel Role Signal Pathway Signal Transduction Signaling Protein Site Study Section Study models Synapses Synaptic Transmission Synaptic Vesicles Testing Vesicle Work base design fly genetic analysis insight mutant postsynaptic presynaptic programs receptor relating to nervous system research study response synaptic function

项目摘要

DESCRIPTION (provided by applicant): Project Summary: The goal of this research is to bridge the gap between synaptic function and the control of behavior by identifying the signaling pathways that control synaptic activity. Our studies of the model organism C. elegans have shown that the integrated activities of 3 major Ga pathways control synaptic activity to produce the locomotion behavior. Within this synaptic signaling network, the neuronal Gccs pathway is an especially critical but poorly understood link between synaptic function and behavior. Despite years of research in multiple model organisms, we do not understand why animals lacking a neuronal Gas pathway are paralyzed. This proposal takes 3 approaches to investigate the core purpose of the neuronal Gas pathway during the execution of behaviors. Aim 1 asks whether and how the Gas pathway affects various synaptic vesicle pools, including a newly discovered pool of membrane contacting vesicles next to the active zone. Aim 2 expands on our startling discovery that high energy light transforms paralyzed mutants lacking a neuronal Gas pathway into hyperactive animals with coordinated locomotion. Our genetic analysis suggests that high energy light activates a pathway that bisects the network downstream of the Gas pathway but upstream of the synaptic vesicle priming machinery. Through a large forward genetic screen, we have isolated 21 Lite mutants defective in this response. We propose to use these mutants to investigate the molecular basis of the presynaptic light response, and thus obtain clues about the molecular targets of the UNC-31/ Gs pathway. Aims 3 and 4 use forward genetic approaches to identify the signals that control activation of the neuronal Gas pathway. To investigate the mutants in Aims 2-4, we first map the mutation and identify the gene that is mutated. We then apply a set of strategies, including genetic pathway analysis, site-of-action studies, electrophysiological and behavioral assays, and immunolocalization experiments, to determine the specific role of each protein in the network. Relevance: The pathways of the synaptic signaling network are found in all animals, from worms to humans. Studies in model organisms such as worms and flies suggest that all behavior, learning, and memory formation occurs through the pathways of this network. However, the connection between the synaptic signaling network pathways and the control of behavior remains unclear. The experiments in this proposal will drive the discovery of critical missing links that are necessary to decipher the underlying logic of the network. Basic insights from our research should provide important clues and drug targets for human neural disorders such as behavioral and psychiatric disorders, depression, hyperactivity, and memory disorders.

描述（由申请人提供）：项目摘要：这项研究的目的是通过识别控制突触活动的信号传导途径来弥合突触功能与控制行为之间的差距。我们对秀丽隐杆线虫模型的研究表明，3个主要GA途径的综合活性控制着突触活动以产生运动行为。在此突触信号网络中，神经元GCC途径是突触功能与行为之间的特别关键但知之甚少的联系。尽管在多种模型生物中进行了多年的研究，但我们不明白为什么缺乏神经元气体途径的动物会瘫痪。该建议采用3种方法来研究行为执行期间神经元气体途径的核心目的。 AIM 1询问气体路径是否以及如何影响各种突触囊泡池，包括新发现的膜池，接触活动区域旁边的囊泡。 AIM 2扩大了我们令人震惊的发现，即高能量光会转化缺乏神经元气体途径的瘫痪突变体进入具有协调的运动的多动动物。我们的遗传分析表明，高能光激活了一条途径，该途径将气体途径下游的网络划分为一分为二，但突触囊泡启动器械的上游。通过大型的正向遗传筛选，我们在此反应中分离了21个Lite突变体。我们建议使用这些突变体研究突触前光反应的分子基础，从而获得有关UNC-31/ GS途径的分子靶标的线索。 AIMS 3和4使用正向遗传方法来识别控制神经元气体途径激活的信号。为了研究目标2-4中的突变体，我们首先绘制突变并确定突变的基因。然后，我们采用一组策略，包括遗传途径分析，行动现场研究，电生理和行为分析以及免疫定位实验，以确定每种蛋白质在网络中的特定作用。相关性：从蠕虫到人类，在所有动物中都发现突触信号网络的途径。诸如蠕虫和苍蝇等模型生物的研究表明，所有行为，学习和记忆形成都是通过该网络的途径进行的。但是，突触信号网络通路和行为控制之间的连接尚不清楚。该提案中的实验将推动发现关键缺失链接，这些链接是破译网络的基础逻辑所必需的。我们研究的基本见解应为人类神经疾病（例如行为和精神疾病，抑郁症，多动症和记忆障碍）提供重要的线索和药物目标。