Translational control in neurons

神经元的翻译控制

• 批准号: 9043196
• 负责人: HENRI TIEDGE
• 金额: $ 35.33万
• 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 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9043196
• 关键词: Address; Animal Model; Autistic Disorder; BC1 RNA; Behavioral; Biochemical; Brain; Competence; Electrophysiology (science); Epilepsy; Equilibrium; Eukaryotic Initiation Factor-4A; Eukaryotic Initiation Factors; Funding; Gene Expression; Goals; Health; Investigation; Maintenance; Molecular; Neuronal Plasticity; Neurons; Output; Pathway interactions; Phosphorylation; Play; Preparation; Protein Biosynthesis; Protein Dephosphorylation; RNA; RNA Binding; Regulation; Repression; Research; Role; Synapses; Testing; Time; Translational Regulation; Translational Repression; Translations; Work; base; derepression; eIF-4B; experience; neuronal excitability; response

 DESCRIPTION (provided by applicant): Translational control of gene expression is a key mechanism in the experience-dependent long-term modulation of neuronal form and function. It is hypothesized that regulatory RNAs play essential roles in the implementation of this mechanism. Synapto-dendritic BC RNAs control neuronal protein synthesis by targeting the translation mechanism through interactions with eukaryotic initiation factors (eIFs). The resulting translational repression is an important component in the molecular management of synaptic strength as lack of BC1 RNA in animal models causes excessive protein synthesis, neuronal hyperexcitability, and a propensity for epileptogenic responses. The elucidation of molecular mechanisms of BC RNA control will continue to constitute a major emphasis of the project "Translational control in neurons." However, while molecular mechanisms are fundamental underpinnings of translational control pathways, it will now become important to move the investigation to the next level by addressing significant open issues that have come to the fore as a result of previous advances. Three fundamental questions are commanding highest priority at this time: (i) how is BC RNA translational control reversibly modulated, (ii) how do neurons implement such modulation in an activity- dependent manner, and (iii) how does this form of molecular regulation impact neuronal function and plasticity? To address these questions, a Research Plan will be implemented in three Specific Aims. The first Aim will test the hypothesis that the phosphorylation status of eIF4B is a determinant of BC RNA binding and translational repression competence. It is further hypothesized that in neurons, BC RNA translational control is subject to activity-dependent modulation via eIF4B phosphorylation changes. This mechanism will be functionally dissected in Aim 2. Aim 3 will be directed at the role of the BC RNA - eIF4B translational control mechanism in neuronal function, excitability, and plasticity. It will be the long-term goal of the planned project to arrive at a molecular-mechanistic understanding of how reversible, activity-dependent translational control is implemented by synapto-dendritic BC RNAs, and how such control supports elemental forms of neuronal functionality.

 描述（通过应用程序提供）：基因表达的翻译控制是经验依赖性的神经元形式和功能的长期调节中的关键机制。假设监管RNA在实施该机制中起着重要作用。通过与真核启动因子（EIF）相互作用来靶向翻译机制，通过靶向翻译机制来控制神经元蛋白的合成。结果 翻译表示是突触强度分子管理中的重要组成部分，因为动物模型中缺乏BC1 RNA会导致过度蛋白质合成，神经元过度兴奋性和癫痫病反应的倾向。 BC RNA控制的分子机制的阐明将继续构成“神经元中翻译控制”项目的主要重点。但是，尽管分子机制是转化控制途径的基本基础，但现在将投资转移到一个新的水平将变得重要，这是通过解决先前进步的重大开放问题来推动的。目前，三个基本问题正优先：（i）BC RNA翻译控制如何可逆地调节；（ii）神经元如何以活动依赖的方式实施这种调节，（iii）这种分子调节形式如何影响神经元功能和可变性？为了解决这些问题，将以三个具体目标实施研究计划。第一个目的将检验以下假设：EIF4B的磷酸化状态是BC RNA结合和转化表达能力的决定。进一步假设，在神经元中，BC RNA翻译控制受到EIF4B磷酸化变化的活性依赖性调节。该机制将在AIM 2中进行功能剖析。AIM 3将针对BC RNA -EIF4B翻译控制机制在神经元功能，兴奋和可塑性中的作用。计划项目的长期目标是对分子机械的理解对可逆的，依赖于活动的转化控制是如何由Synapto Dendritritic BC RNA实施的，以及该控制如何支持神经元功能的元素形式。