Translational control in neurons

 描述(由申请人提供)：基因表达的翻译控制是依赖经验的神经元形态和功能长期调节的关键机制。据推测，调控RNA在这一机制的实施中发挥着至关重要的作用。突触-树突状BC RNA通过与真核细胞起始因子(EIF)相互作用靶向翻译机制来控制神经元蛋白质的合成。由此产生的 翻译抑制是突触强度分子管理的重要组成部分，因为动物模型中缺乏bc1 RNA会导致蛋白质合成过多，神经元过度兴奋，并有致痫反应的倾向。BC RNA控制的分子机制的阐明将继续构成“神经元中的翻译控制”项目的主要重点。然而，尽管分子机制是翻译调控途径的基本基础，但现在重要的是通过解决由于先前的进展而出现的重大开放问题来将研究推向下一个水平。目前有三个基本问题是当务之急：(I)BC RNA翻译控制是如何可逆调节的，(Ii)神经元如何以依赖活动的方式实施这种调节，以及(Iii)这种形式的分子调节如何影响神经元的功能和可塑性？为了解决这些问题，将在三个具体目标中实施一项研究计划。第一个目的是验证eIF4B的磷酸化状态是BC RNA结合和翻译抑制能力的决定因素的假设。进一步假设，在神经元中，BC RNA的翻译控制受到eIF4B磷酸化变化的活性依赖的调节。这一机制将在目标2中进行功能剖析。目标3将针对BC RNA-eIF4B翻译控制机制在神经元功能、兴奋性和可塑性中的作用。计划中的项目的长期目标将是从分子机制上理解突触-树突BC RNA如何实现可逆的、依赖活动的翻译控制，以及这种控制如何支持基本形式的神经元功能。

 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.