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: 7482985
• 负责人: PETER C JUO
• 金额: $ 35.77万
• 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/7482985
• 关键词: Affect; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animals; Biological; Blood flow; Brain; Brain Injuries; Caenorhabditis elegans; Cell physiology; Cells; Chromosome Pairing; 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; Localized; 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; Thinking; Ubiquitin; Ubiquitination; anterograde transport; excitotoxicity; genetic analysis; in vivo; intracellular protein transport; mutant; neuronal cell body; novel; novel therapeutics; postsynaptic; programs; protein transport; synaptic function; therapeutic target; 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）：本研究的长期目标是识别和了解突触传递中调节 CDK-5 功能的基因和机制。细胞周期蛋白依赖性激酶 CDK-5 在发育过程中具有多种细胞功能，导致多种神经退行性疾病，并且最近已成为突触功能和可塑性的重要调节因子。该提案的重点是研究 CDK-5 调节谷氨酸受体 (GluR) 运输的机制，并确定控制突触处 CDK-5 功能的上游调节信号。突触 GluR 的定位和丰度的活动依赖性调节直接影响突触强度，并被认为是大脑中信息存储和处理的基础。 GluR 的异常调节可能导致缺血（血流不足）、中风和神经退行性疾病中的兴奋性毒性。因此，定义调节 GluR 转运的基本细胞生物学机制非常重要。我们使用线虫作为遗传模型来研究体内调节突触传递和 GluR 运输的基因和机制。秀丽隐杆线虫的优点包括基因组紧凑（即基因冗余较少）、强大的遗传工具以及动物耐受神经系统功能严重下降的能力。我们的初步研究表明，CDK-5 调节体内突触处支架蛋白 LIN-10/Mint-1 和谷氨酸受体 GLR-1 的丰度。 LIN-10/Mint-1 是一种含有 PTB 和 PDZ 结构域的蛋白质，定位于高尔基体和突触，在神经元和上皮细胞的极化运输中具有保守的作用。在本提案中，我们将 (1) 确定 GLR-1 运输的哪一步受 CDK-5 调节，(2) 定义 CDK-5 调节 LIN-1u/Mint-1 丰度的机制，(3)表征控制 CDK-5 功能的上游调节信号。这项研究可能揭示治疗干预的新目标，以控制中风和缺血性（血流不足）脑损伤后 GluR 介导的兴奋性毒性。此外，由于 CDK-5 调节神经元发育和功能，并导致阿尔茨海默病和肌萎缩侧索硬化症 (ALS)，因此了解调节 CDK-5 活性的机制以及它如何控制健康神经元中的突触传递将有助于揭示潜在的发病机制。 CDK-5 在神经变性中的作用。