Translational control in neurons

描述（由申请人提供）：非蛋白质编码（npc） rna是控制真核生物基因表达的关键介质。在大脑中，npcRNAs与神经元对外部刺激的长期可塑性反应能力的适应性变化有关。这种能力，据认为，至少部分支持的翻译调节的基因表达在突触。然而，在为突触蛋白库的输入特异性管理提供分子框架的同时，突触翻译的概念取决于分子工具，以确保对翻译机制的严格控制。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，提出了小的npcrna在神经元翻译控制的协调中起着重要作用。具体来说，有人推测突触-树突BC rna通过抑制起始机制参与神经元翻译。这个猜想将在实验上作如下的研究。首先，通过剖析BC1 RNA与其翻译通路靶点真核起始因子4A （eukaryotic initiation factor 4A, eIF4A）之间的功能相互作用，阐明bc介导的抑制的分子机制。本分析还将探讨eIF4A辅助因子eIF4B作为BC1-eIF4A相互作用的效应因子的作用。下一步将确定人BC200 RNA在翻译控制中的作用模式。BC200 RNA是一种灵长类npcRNA，具有翻译抑制因子的功能，可能与神经系统疾病有关。将使用候选和无偏的方法确定bc介导的抑制的神经元靶点。由于BC抑制的功能后果似乎与脆性X智力迟钝蛋白（FMRP）的功能后果交叉，因此有必要确定这两种抑制途径的作用模式和潜在的收敛性。在最后的目标中，我们将仔细研究BC抑制的假设，可以想象，它在MEK/ERK信号通路中起作用，有助于代谢性谷氨酸受体激活引起的突触对翻译刺激的权力平衡。建立npcrna在神经元翻译调控通路中的分子机制和功能意义是本研究的总体目标。预计本研究结果将揭示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BC rna的翻译控制与突触局部刺激-抑制稳态的维持有关。BC1控制失调导致突触高兴奋性和致痫性反应，这些反应似乎与脆性X智力迟钝蛋白缺乏引起的后遗症交叉。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。

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.