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Engineered Regulated RNA Localization and Transport in Biological Systems

生物系统中工程调控的 RNA 定位和运输

基本信息

批准号：
7981032
负责人：
JACQUIN C NILES
金额：
$ 251.25万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2015-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (Provided by the applicant) Abstract: Evidence is rapidly accumulating in support of specific and functionally significant sub- cellular mRNA localization in many organisms. Transcript localization shapes many fundamental processes including cell polarity, migration and neuronal activity, and impacts diverse biological processes such as development, memory and learning. Although attention has been focused on localization of a few selected transcripts, recent global analyses indicate that the phenomenon is extremely common. In many cases, different transcripts are observed to have distinct sub-cellular spatial localization patterns. Several prominent examples of specific transcript localization shaping processes such as body axis polarity in Drosophila and synaptic plasticity in neurons suggest the potential for there being direct functional significance of transcript localization, now recognized to be a commonly observed phenomenon. Unfortunately, we have very limited understanding of the protein factors required for achieving specific transcript localization patterns. Moreover, we lack strategies for selectively perturbing transcript spatial distribution in a manner compatible with understanding the associated functional consequences. This proposal addresses these needs by introducing a method permitting regulated targeting of a given transcript to a sub-cellular location, the latter being driven by known or putative localization factors under evaluation. In this approach, transcript localization is entirely experimentally controlled, and is conditional upon either small molecule or peptide signals applied to target cells using high-resolution chemical gradients and post-translational protein localizing modifications, respectively. This broadly applicable method has the potential to advance our basic knowledge of the cellular mechanisms underlying transcript localization, and to probe the associated functional implications at both the cellular and organism levels. Public Health Relevance: Sub-cellular RNA localization into discrete, transcript-dependent patterns is now recognized to be a widespread phenomenon in many cell types and organisms, including humans. In several well-studied cases, transcript localization is required for establishing proper cellular function, and defects in this process contribute to developmental, cognitive and other neurological problems in humans. The proposed research will introduce new methods for understanding and manipulating the mechanisms underlying RNA sub-cellular localization, and has the potential to improve both our understanding and treatment of disease processes associated with RNA localization defects.

描述（由申请人提供）摘要：越来越多的证据支持在许多生物体中存在特定且具有功能意义的亚细胞 mRNA 定位。转录本定位塑造了许多基本过程，包括细胞极性、迁移和神经元活动，并影响多种生物过程，如发育、记忆和学习。尽管人们的注意力集中在一些选定转录本的本地化上，但最近的全球分析表明这种现象极为普遍。在许多情况下，观察到不同的转录本具有不同的亚细胞空间定位模式。特定转录本定位塑造过程的几个突出例子，例如果蝇的体轴极性和神经元的突触可塑性，表明转录本定位可能具有直接的功能意义，现在被认为是一种常见的观察到的现象。不幸的是，我们对实现特定转录本定位模式所需的蛋白质因素的了解非常有限。此外，我们缺乏以与理解相关功能后果相一致的方式选择性扰乱转录本空间分布的策略。该提案通过引入一种允许将给定转录本调节靶向亚细胞位置的方法来满足这些需求，后者由正在评估的已知或推定的定位因素驱动。在这种方法中，转录本定位完全是通过实验控制的，并且以分别使用高分辨率化学梯度和翻译后蛋白质定位修饰应用于靶细胞的小分子或肽信号为条件。这种广泛适用的方法有可能增进我们对转录本定位的细胞机制的基本了解，并在细胞和生物体水平上探讨相关的功能含义。公共健康相关性：亚细胞 RNA 定位为离散的转录依赖性模式现已被认为是许多细胞类型和生物体（包括人类）中的普遍现象。在一些经过充分研究的案例中，转录本定位对于建立适当的细胞功能是必需的，而这个过程中的缺陷会导致人类的发育、认知和其他神经系统问题。拟议的研究将引入新的方法来理解和操纵RNA亚细胞定位的机制，并有可能提高我们对与RNA定位缺陷相关的疾病过程的理解和治疗。