Molecular and genetic analysis of CDK-5 function in synaptic transmission

CDK-5在突触传递中的功能的分子和遗传学分析

基本信息

批准号：
8678130
负责人：
PETER C JUO
金额：
$ 41.25万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-15 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8678130
关键词：
3&apos Untranslated Regions Airborne Particulate Matter Alzheimer&apos s Disease Aplysia Binding Binding Sites Biological Brain Caenorhabditis elegans Cell Death Cell membrane Cell surface Cells Clathrin Complex Coupled Data Deubiquitinating Enzyme Development Dynein ATPase Endocytosis Endosomes Epilepsy Excision Exocytosis Genes Genetic Genetic Models Glutamate Receptor Glutamates Goals Image Ischemia Kinesin Lead Learning Light Link Lysosomes Mediating Memory Mental Depression Messenger RNA MicroRNAs Modeling Molecular Molecular Analysis Motor Mus Mutation Neurodegenerative Disorders Neurons Neurotransmitter Receptor Neurotransmitters Pathway interactions Phosphorylation Phosphotransferases Positioning Attribute Process Protein Kinase Proteins Receptor Cell Regulation Regulatory Pathway Research Stroke Synapses Synaptic Transmission Synaptic plasticity Testing Transcription Factor AP-2 Alpha Ubiquitin anterograde transport base excitotoxicity genetic analysis in vivo insight motor control nervous system disorder neuronal cell body novel postsynaptic prevent therapeutic target time use trafficking ubiquitin ligase

项目摘要

DESCRIPTION (provided by applicant): Glutamate is the major excitatory neurotransmitter in the brain. Activity-dependent changes in the abundance of AMPA-type glutamate receptors (GluRs) at synapses can alter synaptic strength and are a major cellular mechanism involved in learning and memory. Aberrant regulation of GluRs contributes to excitotoxic cell death in ischemia, stroke and several neurodegenerative disorders. Thus it is important to understand the cell biological and molecular mechanisms involved in regulating GluR localization and abundance at synapses. The long-term goal of this research is to define genes and mechanisms that regulate the abundance of GluRs at synapses. Great progress has been made in our understanding of the mechanisms involved in AMPAR insertion (exocytosis) and removal (endocytosis) at synapses. However, much less is known about the motors and adaptors that regulate anterograde trafficking of GluRs from the cell body to the synapse. The focus of this proposal is to understand the fundamental mechanisms involved in regulating motor-dependent transport of GluRs from cell bodies to synapses. We use C. elegans as a genetic model to study genes and mechanisms that regulate the trafficking of GluRs in vivo. We recently showed that the protein kinase CDK-5 promotes anterograde trafficking of GLR-1, a C. elegans GluR, and that the kinesin 3 motor KLP-4/KIF13 is required for this effect. In preliminary studies, we identify two microRNAs (miR-75 and miR-79), and the AP2 clathrin adaptin subunit APM-2/¿2, as novel regulators of GLR-1 anterograde transport. We also discovered that GLR-1 stability may be coupled to KLP-4-dependent anterograde transport. In this proposal, Aim 1 will investigate a novel function for APM-2/¿2 in the anterograde trafficking of GluRs. Aim 2 will investigate mechanisms by which the kinase CDK-5 and microRNAs regulate KLP-4-dependent trafficking. Aim 3 will investigate mechanisms that couple KLP-4-dependent anterograde transport to GLR- 1 degradation. Identifying genes and mechanisms that regulate GluR levels at synapses may provide potential therapeutic targets for reducing GluR-mediated excitotoxicity after stroke and ischemia.

描述（由申请人提供）：谷氨酸是大脑中主要的兴奋性神经递质，突触处 AMPA 型谷氨酸受体 (GluR) 丰度的活动依赖性变化可以改变突触强度，并且是参与学习和记忆的主要细胞机制。 GluR 的异常调节会导致缺血、中风和多种神经退行性疾病中的兴奋性毒性细胞死亡，因此了解细胞的生物学和功能非常重要。参与调节突触 GluR 定位和丰度的分子机制这项研究的长期目标是定义调节突触 GluR 丰度的基因和机制，在我们对 AMPAR 插入机制的理解方面取得了巨大进展。然而，对于调节 GluR 从细胞体顺行运输到突触的马达和适配器知之甚少。该提案的重点是了解调节 GluR 从细胞体到突触的运动依赖性运输的基本机制。我们使用秀丽隐杆线虫作为遗传模型来研究调节体内 GluR 运输的基因和机制。我们最近表明，蛋白激酶 CDK-5 促进 GLR-1（一种线虫 GluR）的顺行运输，并且驱动蛋白 3 马达在初步研究中，我们确定了两种 microRNA（miR-75 和 miR-79）和 AP2 网格蛋白适应素亚基 APM-2/¿ 2，作为 GLR-1 顺行运输的新型调节剂我们还发现 GLR-1 稳定性可能与 KLP-4 依赖性顺行运输耦合。在本提案中，目标 1 将研究 APM-2/¿ 2 在 GluR 顺行运输中的作用目标 2 将研究激酶 CDK-5 和 microRNA 调节 KLP-4 依赖性运输的机制目标 3 将研究将 KLP-4 依赖性顺行运输与 GLR-1 降解相结合的机制。鉴定调节突触 GluR 水平的基因和机制可能为减少中风和缺血后 GluR 介导的兴奋性毒性提供潜在的治疗靶点。