Importin-mediated signaling from synapse to nucleus during neuronal plasticity

神经元可塑性过程中输入蛋白介导的从突触到细胞核的信号传导

• 批准号: 7802314
• 负责人: Kelsey C Martin
• 金额: $ 32.73万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-05 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7802314
• 关键词: Acute; Address; Adult; Alzheimer' s Disease; Anxiety; Binding; Biological; Brain; Carrier Proteins; Cell Nucleus; Cells; Communication; Complex; Dendrites; Dependence; Development; Disease; Distal; Docking; Drug Addiction; Epilepsy; Gene Expression; Genetic Transcription; Growth Cones; Hippocampus (Brain); Importins; Information Storage; Lead; Learning; Mass Spectrum Analysis; Mediating; Memory; Memory Loss; Mental Retardation; Mood Disorders; Mus; Natural regeneration; Neuronal Plasticity; Neurons; Nuclear; Nuclear Import; Nuclear Localization Signal; Nuclear Pore; Pathologic Processes; Pathway interactions; Physiological; Protein Biosynthesis; Proteins; Proteomics; Public Health; RNA; Regulation; Role; Signal Transduction; Slice; Stimulus; Synapses; Synaptic plasticity; Travel; age related; alpha Karyopherins; design; drug of abuse; experience; injured; injury and repair; nerve injury; neuronal cell body; neuropsychiatry; nucleocytoplasmic transport; protein transport; research study; therapeutic target; trafficking; transcription factor

DESCRIPTION (provided by applicant): Synaptic plasticity, changes in the strength of connections between neurons with experience, provides a mechanism for information storage in the brain. Long-lasting forms of plasticity have been shown to require RNA and protein synthesis, indicating that signals can be transported from the synapse, where they are generated, to the nucleus, where they are converted into changes in gene expression. The extreme polarity of neurons and the significant distances that can exist between distal synapses and cell soma present a unique set of challenges to nucleocytoplasmic trafficking. The aim of this proposal is to delineate the role of the active nuclear import pathway in transporting signals from synapse to nucleus during long-lasting forms of learning-related synaptic plasticity. In this pathway, proteins bearing nuclear localization signals (NLSs) are recognized by a nuclear transport adaptor, called importin alpha, which then binds a nuclear transporter called importin betal. Importin betal docks the heterotrimeric complex at the nuclear pore and mediates its translocation into the nucleus. We plan to study importin-mediated nuclear transport, using both dissociated mouse hippocampal cultures and acute hippocampal slices to study various aspects of synaptic plasticity. In our first aim, we will determine whether importins are localized to the synapse and subsequently translocate following stimuli that lead to transcription-dependent plasticity. In the second aim, we propose to identify synaptically localized proteins that are transported to the nucleus following synaptic stimulation. In the final aim, we will determine how the importin-cargo complex is assembled at the synapse and what cell biological pathways are involved in the translocation of this complex to the nucleus. Relevance to public health: Understanding the mechanisms whereby synaptically generated signals trigger changes in gene expression in the nucleus during memory formation provides a means of identifying therapeutic targets for a variety of disorders including mental retardation, age-related memory loss, Alzheimer's disease, epilepsy, drug addiction as well as many neuropsychiatric diseases.

描述（由申请人提供）：突触可塑性，神经元与经验的连接强度的变化，为大脑中的信息存储提供了一种机制。长期的可塑性形式已显示需要RNA和蛋白质合成，表明信号可以从突触（生成的地方）传输到细胞核，并将它们转化为基因表达的变化。神经元的极端性以及远端突触和细胞体之间可能存在的显着距离提出了对核质流量的独特挑战。该提议的目的是描述活跃的核进口途径在与学习相关的突触可塑性形式中从突触中传输信号到核的作用。在这一途径中，带有核定位信号（NLS）的蛋白质被称为Importin Alpha的核转运适配器认可，该适配器随后结合了一种称为Importal的核转运蛋白。 Importin betal在核孔隙中停靠了异三聚体配合物，并将其易位转移到细胞核中。我们计划使用解离的小鼠海马培养物和急性海马切片研究进口素介导的核转运，以研究突触可塑性的各个方面。在我们的第一个目标中，我们将确定导入蛋白是否定位于突触，随后在导致转录依赖性可塑性的刺激之后转移。在第二个目标中，我们建议鉴定突触刺激后转运到细胞核的突触局部蛋白质。在最终目的中，我们将确定如何在突触处组装进口素 - 碳酸盐复合物，以及该复合物转移到核的转运中涉及哪些细胞生物学途径。与公共卫生的相关性：了解在记忆形成过程中突触产生的信号触发基因表达的信号变化的机制提供了一种识别各种疾病的治疗靶标的方法，包括精神降低，与年龄相关的记忆丧失，阿尔茨海默氏病，阿尔茨海默氏病，癫痫病，药物成瘾以及许多神经精神疾病。