Small RNAs in Neurons

描述(申请人提供)：在神经元中，局部蛋白质合成是调节突触强度的重要工具。这一机制的特异性至少部分取决于本地可用于现场翻译的mRNAs的特性。因此，靶向向突触树突状结构域递送特定的RNA是神经元功能和可塑性的关键基础。因此，我们必须了解分子信息编码机制，该机制指定和实施树突状靶向神经元RNA。尽管近年来取得了进展，但我们对树突状RNA靶向机制的了解仍处于初级阶段。在最基本的水平上，我们需要识别和理解RNA用来指定突触树突状递送的密码。我们需要破译条件代码，即那些包含在RNA靶向元件中的指定可诱导靶向的代码。我们需要深入了解靶向因子用来解码这些元素的机制，并以依赖于活动的方式启动靶向。为了解决神经细胞生物学中的这些关键问题，拟议的项目将对树突状RNA靶向机制的分子和细胞基础进行功能剖析。计划中的研究将针对最重要的假设，即非规范RNA基序作为树突状靶向密码决定因素。具体地说，目标1将解决非规范靶向基序亚型是否携带离散空间代码的问题，这些离散空间代码是条件树突状RNA运输与构成树突状RNA运输的决定因素。目的2将检验这样的假设，即基序密码是由同源树突靶向因子识别的，而差异识别指定了条件运输与构成运输。目的3将确定这些基序介导的条件性树突状RNA靶向是否可由神经元活动和受体激活诱导。计划中的项目的长期目标将是达成对神经元机制的分子理解，这些机制介导树突中活性依赖的RNA运输。

DESCRIPTION (provided by applicant): In neurons, local protein synthesis is an important instrument in the modulation of synaptic strength. The specificity of this mechanism is determined, at least in part, by the identity of mRNAs that are locally available for on-site translation. The targeted delivery of select RNAs to synapto-dendritic domains is therefore a key underpinning of neuronal function and plasticity. For this reason, it is essential that we understand molecular information coding mechanisms that specify and implement dendritic targeting of neuronal RNAs. Our understanding of dendritic RNA targeting mechanisms has remained rudimentary, despite progress in recent years. At a most fundamental level, we need to identify and comprehend the codes that are used by RNAs to specify synapto-dendritic delivery. We need to decipher conditional codes, i.e. those contained in RNA targeting elements that specify inducible targeting. We need to gain insight into mechanisms that targeting factors use to decode such elements and initiate targeting in an activity-dependent manner. To address these critical issues in neuronal cell biology, the proposed project will conduct a functional dissection of the molecular and cellular basis of dendritic RNA targeting mechanisms. The planned research will be directed at the overarching hypothesis that noncanonical RNA motifs serve as dendritic targeting code determinants. Specifically, Aim 1 will address the question whether noncanonical targeting motif subtypes carry discrete spatial codes that are determinants of conditional vs. constitutive dendritic RNA transport. Aim 2 will test the hypothesis that motif codes are recognized by cognate dendritic targeting factors, and that differential recognition specifies conditional vs. constitutive transport. Aim 3 will establish whether conditional dendritic RNA targeting mediated by such motifs is inducible by neuronal activity and receptor activation. It will be the long-term goal of the planned project to arrive ata molecular understanding of neuronal mechanisms that mediate activity-dependent RNA transport in dendrites.