Translational control in neurons

描述（由申请人提供）：非蛋白编码（npc）RNA是控制真核基因表达的关键介质。在大脑中，npcRNA与适应性变化有关，这种适应性变化是神经元对外部刺激进行长期塑性反应的能力的基础。这种能力，它建议，至少部分地支持在突触的基因表达的翻译调节。然而，虽然提供了一个分子框架的输入特异性管理的突触蛋白库，突触翻译的概念是视情况而定的分子工具，以确保严格控制的翻译机器。实现这种控制的功能机制是什么，它们在神经元中是如何调节的？在这里提出的研究中，有人认为小npcRNA在神经元翻译控制的协调中起着重要作用。具体地说，它是明确的，突触树突状BC RNA参与神经元的翻译抑制的起始机制。这个猜想将被实验研究如下。首先，BC介导的抑制的分子机制将阐明通过解剖BC 1 RNA和其在翻译途径中的目标，真核起始因子4A（eIF 4A）之间的功能相互作用。该分析还将探索eIF 4 B（eIF 4A辅因子）作为BC 1-eIF 4A相互作用的效应子的作用。随后的步骤将建立人BC 200 RNA在翻译控制中的作用模式。这一努力是由BC 200 RNA这一灵长类动物npcRNA作为翻译阻遏物的功能可能与神经系统疾病有关的概念所推动的。将使用候选和无偏倚的方法鉴定BC介导的抑制的神经元靶标。由于BC抑制的功能后果似乎与脆性X智力低下蛋白（FMRP）的功能后果相交，因此有必要确定两种抑制途径的作用模式和潜在的收敛性。在最后的目标，该假设将被仔细审查，BC的镇压，可以想象的MEK/ERK信号通路中的操作，有助于突触的功率平衡维斯-vis-维斯由代谢型谷氨酸受体激活引起的翻译刺激。本研究的总体目标是建立npcRNA在神经元翻译控制通路中的分子机制和功能意义。预计这项工作的结果将阐明这些通路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，突触-树突状BC RNA的翻译控制与突触局部刺激-抑制稳态的维持有关。BC 1控制的失调沉淀了突触过度兴奋和癫痫反应，这些反应似乎与缺乏脆性X精神发育迟滞蛋白引起的后遗症相交。因此，BC控制失调的功能后果与神经和精神障碍的生物学直接相关。

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.