Small RNAs in Neurons

描述（由申请人提供）：在神经元中，局部蛋白质合成是调节突触强度的重要工具。该机制的特异性至少部分地由可局部用于原位翻译的mRNA的身份决定。因此，将选择RNA靶向递送至突触-树突结构域是神经元功能和可塑性的关键基础。出于这个原因，我们必须了解指定和实现神经元RNA的树突靶向的分子信息编码机制。 尽管近年来取得了进展，但我们对树突状RNA靶向机制的理解仍然是初步的。在最基本的层面上，我们需要识别和理解RNA用于指定突触-树突传递的代码。我们需要破译条件代码，即那些包含在RNA靶向元件中的指定诱导型靶向的代码。我们需要深入了解靶向因子用于解码这些元素并以依赖于活性的方式启动靶向的机制。为了解决神经元细胞生物学中的这些关键问题，拟议的项目将进行树突状RNA靶向机制的分子和细胞基础的功能解剖。 计划中的研究将针对非经典RNA基序作为树突状靶向密码决定簇的总体假设。具体来说，目标1将解决的问题是否非典型的靶向基序亚型携带离散的空间代码，是条件性与组成性树突状RNA运输的决定因素。目标2将测试的假设，基序代码被识别的同源树突状靶向因子，和差异识别指定条件与组成性运输。目的3将建立是否有条件的树突状RNA靶向介导的这些图案是可诱导的神经元活动和受体激活。这将是计划中的项目的长期目标，以达到一个分子的理解神经元机制，介导活动依赖的RNA运输在树突。

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.