Translational control in neurons

神经元的翻译控制

• 批准号: 8128966
• 负责人: HENRI TIEDGE
• 金额: $ 4.36万
• 依托单位: SUNY DOWNSTATE MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8128966
• 关键词: ATP phosphohydrolase; Action Potentials; Acute; BC1 RNA; Biology; Brain; Code; Competence; Complex; Data; Ensure; Epilepsy; Equilibrium; Eukaryotic Initiation Factor-4A; Feedback; Fragile X Mental Retardation Protein; Functional disorder; Gene Expression; Genes; Genetic; Goals; Homeostasis; Human; In Vitro; Light; MEKs; Maintenance; Mediating; Mediator of activation protein; Mental disorders; Messenger RNA; Metabotropic Glutamate Receptors; MicroRNAs; Molecular; Neurologic; Neurologic Dysfunctions; Neurons; Orthologous Gene; Pathway interactions; Phylogenetic Analysis; Physiological; Plastics; Play; Primates; Protein Biosynthesis; Proteins; RNA; RNA Helicase; Receptor Activation; Repression; Research; Role; Series; Signal Pathway; Signal Transduction; Small RNA; Stimulus; Structure; Synapses; Synaptic plasticity; Testing; Translation Initiation; Translational Regulation; Translational Repression; Translations; Untranslated Regions; Work; base; eIF-4B; experience; helicase; in vivo; nervous system disorder; postsynaptic; prevent; progenitor; public health relevance; response; tool

DESCRIPTION (provided by applicant): Non-protein-coding (npc) RNAs are key mediators in the control of eukaryotic gene expression. In brain, npcRNAs have been implicated in adaptive changes that underlie a neuron's capacity for long-term plastic responses to external stimuli. Such capacity, it is suggested, is supported at least in part by the translational regulation of gene expression at the synapse. However, while providing a molecular framework for the input-specific management of synaptic protein repertoires, the concept of synaptic translation is contingent upon molecular tools to ensure stringent control of the translational machinery. What are the functional mechanisms to implement such control, and how are they regulated in neurons? In the research proposed here, it is submitted that small npcRNAs are instrumental in the orchestration of neuronal translational control. Specifically, it is conjectured that synapto-dendritic BC RNAs engage neuronal translation by repressing the initiation mechanism. This conjecture will be experimentally investigated as follows. First, the molecular mechanism of BC-mediated repression will be elucidated by dissecting the functional interplay between BC1 RNA and its target in the translation pathway, eukaryotic initiation factor 4A (eIF4A). This analysis will also probe the role of eIF4B, an eIF4A co-factor, as an effector of BC1-eIF4A interactions. The subsequent step will establish the mode of action of human BC200 RNA in translational control. This effort is prompted by the notion that BC200 RNA, a primate npcRNA that functions as a translational repressor, may be implicated in neurological disease. Neuronal targets of BC-mediated repression will be identified using candidate and unbiased approaches. Because the functional consequences of BC repression appear to intersect with those of the fragile X mental retardation protein (FMRP), it will be necessary to ascertain mode of action and potential convergence of the two repression pathways. In the final objective, the hypothesis will be scrutinized that BC repression, conceivably operating in the MEK/ERK signaling pathway, contributes to a synaptic balance of power vis-¿-vis translational stimulation resulting from metabotropic glutamate receptor activation. It is the overall goal of the proposed research to establish molecular mechanisms and functional significance of npcRNAs in neuronal translational control pathways. It is anticipated that results from this work will shed light on the role of such pathways in synaptic plasticity maintenance and dysfunction. PUBLIC HEALTH RELEVANCE: In neurons, translational control by synapto-dendritic BC RNAs has been implicated in the maintenance of local stimulation-repression homeostasis at the synapse. Dysregulation of BC1 control precipitates synaptic hyperexcitability and epileptogenic responses that appear to intersect with sequelae resulting from lack of fragile X mental retardation protein. The functional consequences of dysregulated BC control are therefore of direct relevance to the biology of neurological and mental disorders.

描述（由应用程序提供）：非蛋白质编码（NPC）RNA是控制真核基因表达的关键介体。在大脑中，NPCRNA在适应性变化中已隐含，这是神经元对外部刺激的长期塑性反应能力的基础。建议至少部分由突触中基因表达的翻译调节支持这种能力。但是，在为突触蛋白库的投入特定管理提供分子框架时，突触翻译的概念取决于分子工具，以确保对转化机械的严格控制。实施这种控制的功能机制是什么？如何在神经元中调节？在此处提出的研究中，据认为，小的NPCRNA在神经元转化控制的编排中起了重要作用。具体而言，猜想是通过反映主动机制来吸引神经元翻译。该概念将在实验中进行，如下所示。首先，将通过在翻译途径中剖析BC1 RNA及其靶标之间的功能相互作用，即真核启动因子因子4a（EIF4A），阐明BC介导的表示的分子机制。该分析还将探测EIF4B（EIF4A共同因素）作为BC1-EIF4A相互作用的效应子的作用。随后的步骤将建立人类BC200 RNA在翻译控制中的作用方式。这种努力是由以下观点促成的，即在神经系统疾病中可以实施BC200 RNA，即功能为翻译代表的主要NPCRNA。 BC介导的表示的神经元靶标将使用候选和公正的方法确定。由于BC表达的功能后果似乎与脆弱的X智力低下蛋白（FMRP）相交，因此有必要确定两个表达途径的作用方式和潜在收敛。在最终目标中，将审查该假设，即可能在MEK/ERK信号通路中起作用的BC表达有助于功率相关的突触平衡-VIS -VIS转化刺激导致代替性谷氨酸受体受体激活产生。该研究的总体目标是建立NPCRNA在神经元翻译控制途径中的分子机制和功能意义。预计这项工作的结果将阐明这种途径在突触可塑性维持和功能障碍中的作用。公共卫生相关性：在神经元中，Synapto Dendritic BC RNA的翻译控制已在Synapse的局部仿真抑制稳态维持中实施。 BC1控制精度合成过度刺激性和癫痫病反应的失调似乎与缺乏脆弱的X智力低下蛋白相交的后遗症相交。因此，BC控制失调的功能后果与神经和精神疾病的生物学直接相关。