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

• 批准号: 7804481
• 负责人: PETER C JUO
• 金额: $ 35.41万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7804481
• 关键词: Affect; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animals; Biological; Blood flow; Brain; Brain Injuries; Caenorhabditis elegans; Cell physiology; Cells; Chronic; Cyclin-Dependent Kinases; Data; Development; Endoplasmic Reticulum; Epithelium; Figs - dietary; Genes; Genetic; Genetic Models; Genome; Genus Mentha; Glutamate Receptor; Goals; Golgi Apparatus; Human; In Vitro; Information Storage; Ischemia; Ischemic Stroke; Lobular Neoplasia; Mediating; Membrane; Molecular Genetics; Nerve Degeneration; Nervous System Physiology; Neurodegenerative Disorders; Neurons; Pathogenesis; Pathway interactions; Phosphorylation Site; Phosphotransferases; Process; Proteins; Recycling; Regulation; Reiterated Genes; Research; Research Personnel; Role; Scaffolding Protein; Signal Transduction; Sorting - Cell Movement; Stroke; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Therapeutic Intervention; Ubiquitin; Ubiquitination; anterograde transport; excitotoxicity; genetic analysis; in vivo; mutant; neuron development; neuronal cell body; new therapeutic target; novel; postsynaptic; programs; protein transport; synaptic function; tool; trafficking; ubiquitin ligase

DESCRIPTION (provided by applicant): The long-term goal of this research is to identify and understand the genes and mechanisms that regulate CDK-5 function in synaptic transmission. The cyclin-dependent kinase CDK-5 has diverse cellular functions during development, contributes to several neurodegenerative disorders, and has recently emerged as an important regulator of synapse function and plasticity. The focus of this proposal is to investigate the mechanisms by which CDK-5 regulates glutamate receptor (GluR) trafficking and to identify upstream regulatory signals that control CDK-5 function at the synapse. Activity-dependent regulation of the localization and abundance of synaptic GluRs directly affects synaptic strength and is thought to underlie information storage and processing in the brain. Aberrant regulation of GluRs may contribute to excitotoxicity in ischemia (lack of blood flow), stroke and neurodegenerative disorders. Thus, it is important to define the basic cell biological mechanisms that regulate GluR transport. We use C. elegans as a genetic model to study the genes and mechanisms that regulate synaptic transmission and GluR trafficking in vivo. Advantages of C. elegans include the compact genome (i.e. less gene redundancy), powerful genetic tools and ability of the animal to tolerate severe reductions in nervous system function. Our preliminary studies indicate that CDK-5 regulates the abundance of the scaffolding protein LIN-10/Mint-1 and the glutamate receptor GLR-1 at synapses in vivo. LIN-10/Mint-1 is a PTB and PDZ domain-containing protein that has been localized to the golgi and synapses and has a conserved role in polarized transport in neurons and epithelia. In this proposal, we will (1) Determine which step of GLR-1 trafficking is regulated by CDK-5, (2) Define the mechanisms by which CDK-5 regulates the abundance of LIN-1u/Mint-1, (3) Characterize the upstream regulatory signals that control CDK-5 function. This research may reveal novel targets for therapeutic intervention to control GluR-mediated excitotoxicity after stroke and ischemic (lack of blood flow) brain injury. In addition, since CDK-5 regulates neuronal development and function, and contributes to Alzheimer's Disease and amyotrophic lateral sclerosis (ALS), understanding the mechanisms that regulate CDK-5 activity and how it controls synaptic transmission in healthy neurons will help reveal the pathogenesis underlying the role of CDK-5 in neurodegeneration.

描述（由申请人提供）：这项研究的长期目标是识别和理解调节突触传播中CDK-5功能的基因和机制。依赖细胞周期蛋白的激酶CDK-5在发育过程中具有不同的细胞功能，导致了几种神经退行性疾病，并且最近成为突触功能和可塑性的重要调节剂。该提案的重点是研究CDK-5调节谷氨酸受体（GLUR）运输的机制，并确定控制突触中CDK-5功能的上游调节信号。依赖活性的调节和突触胶的丰度直接影响突触强度，被认为是大脑中信息存储和处理的基础。异常的gl胶调节可能导致缺血（缺乏血流），中风和神经退行性疾病的兴奋性毒性。因此，重要的是定义调节Glur转运的基本细胞生物学机制。我们使用秀丽隐杆线虫作为遗传模型来研究调节体内突触传播和Glur贩运的基因和机制。秀丽隐杆线虫的优势包括紧凑的基因组（即基因的冗余较少），强大的遗传工具以及动物耐受严重降低神经系统功能的能力。我们的初步研究表明，CDK-5调节体内突触中的脚手架蛋白LIN-10/MINT-1和谷氨酸受体GLR-1的丰度。 LIN-10/MINT-1是含PTB和PDZ结构域的蛋白质，已定位在高尔基体和突触中，并且在神经元和上皮中的极化转运中具有保守的作用。在此提案中，我们将（1）确定CDK-5调节GLR-1运输的哪个步骤，（2）定义了CDK-5调节LIN-1U/MINT-1的丰度的机制，（3）表征了控制CDK-5功能的上游调节信号。这项研究可能揭示了治疗干预措施的新靶标，以控制中风和缺血性（缺乏血液流动）脑损伤后Glur介导的兴奋性毒性。此外，由于CDK-5调节神经元的发育和功能，并有助于阿尔茨海默氏病和肌萎缩性侧面硬化症（ALS），因此了解调节CDK-5活性的机制及其控制在健康神经元中的突触传播的机制将有助于揭示CDK-5 IN NEURODEGENERALISALISION CDK-5的病原体。