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（申请人提供）摘要：证据正在迅速积累，以支持许多生物体中特定和功能显着的亚细胞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，并影响多种生物学过程，例如发展，记忆和学习。尽管注意力集中在一些选定的成绩单的定位上，但最近的全球分析表明，这种现象非常普遍。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。特定转录定位过程的几个突出的例子，例如果蝇中的身体轴极性和神经元中突触可塑性，这表明具有转录本定位的直接功能意义的潜力，现在被认为是通常观察到的现象。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子的理解非常有限。此外，我们缺乏与理解相关功能后果兼容的方式选择性扰动转录空间分布的策略。该提案通过引入允许对给定笔录进行调节的方法来解决这些需求，后者是由评估中的已知或推定定位因子驱动的。在这种方法中，转录本的定位完全是实验控制的，并且是基于使用高分辨率化学梯度和翻译后蛋白质定位修饰的小分子或肽信号的条件。这种广泛适用的方法有可能提高我们对成绩单定位基础的细胞机制的基本知识，并探测细胞和生物水平上相关的功能含义。公共卫生相关性：细胞亚细胞RNA定位到离散的成绩单依赖性模式中，现在被认为是包括人类在内的许多细胞类型和生物中的广泛现象。在几个良好的情况下，建立适当的细胞功能需要成绩单定位，并且在此过程中的缺陷有助于人类的发育，认知和其他神经问题。拟议的研究将引入新的方法，以理解和操纵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。