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: 7617010
• 负责人: Kelsey C Martin
• 金额: $ 32.36万
• 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/7617010
• 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，神经元之间连接强度随经验的变化，为大脑中的信息存储提供了一种机制。长期存在的可塑性形式需要RNA和蛋白质的合成，这表明信号可以从产生信号的突触传递到细胞核，在那里它们被转化为基因表达的变化。神经元的极端极性以及远端突触和细胞索马之间可能存在的显著距离对核质运输提出了一系列独特的挑战。这个建议的目的是描绘的作用，积极的核输入途径在运输信号从突触到核在长期持久的形式学习相关的突触可塑性。在该途径中，携带核定位信号（NLS）的蛋白质被称为输入蛋白α的核转运衔接子识别，然后结合称为输入蛋白β 1的核转运蛋白。输入蛋白β 1将异源三聚体复合物停靠在核孔处并介导其易位到核中。我们计划研究输入蛋白介导的核转运，使用解离的小鼠海马培养物和急性海马切片来研究突触可塑性的各个方面。在我们的第一个目标，我们将确定是否importins本地化的突触，随后易位以下刺激，导致转录依赖的可塑性。在第二个目标中，我们建议识别突触局部化的蛋白质，这些蛋白质在突触刺激后被转运到细胞核。在最后的目标，我们将确定如何在突触组装的importin-cargo复合物和什么样的细胞生物学途径参与了这个复杂的易位到细胞核。与公共卫生的相关性：了解记忆形成过程中突触产生的信号触发细胞核基因表达变化的机制，为识别各种疾病的治疗靶点提供了一种手段，这些疾病包括精神发育迟滞、年龄相关性记忆丧失、阿尔茨海默病、癫痫、药物成瘾以及许多神经精神疾病。