Functional genomics of the dynamic molecular network controlling mRNA translation and decay

控制 mRNA 翻译和衰变的动态分子网络的功能基因组学

基本信息

批准号：
10116424
负责人：
NICHOLAS T INGOLIA
金额：
$ 30.45万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10116424
关键词：
Address Affect Binding Binding Proteins Catalogs Cell physiology Cells Complement Cues Cytosol Disease Environment Gene Expression Genes Genetic Genetic Transcription Genetic Translation Goals Growth Homeostasis Human Individual Learning Link Mammalian Cell Maps Measures Mediating Messenger RNA Modeling Molecular Pathologic Phosphorylation Physiological Physiological Adaptation Physiology Play Post-Transcriptional Regulation Proteins RNA RNA Binding RNA-Binding Proteins RNA-Protein Interaction Regulation Regulon Role Saccharomycetales Signal Pathway Signal Transduction Stimulus Stress Surveys Switch Genes Techniques Transcript Translations Work base biological systems disease phenotype environmental change environmental stressor functional genomics genetic regulatory protein in vivo insight mRNA Decay new therapeutic target programs protein profiling response transcription factor

项目摘要

ABSTRACT Cells respond to environmental changes and stresses by modulating the translation and decay of mRNAs in the cytosol. This post-transcriptional regulation is critical for maintaining proper cellular physiology. Often, these regulatory programs protect cells from pathological stresses. In other cases, however, maladaptive responses underlie disease phenotypes. Understanding these dynamic, environmentally responsive post-transcriptional regulatory programs is critical for understanding cell physiology and promises novel therapeutic targets to support protective responses and suppress damaging ones. Recent work has catalogued hundreds of mRNA-binding proteins. Our understanding of how these proteins affect the mRNAs they bind has lagged behind studies that enumerate these proteins, and we generally lack an understanding of their broader role in the cell. Our motivating hypothesis is that many of these proteins target speciﬁc transcripts and regulate their translation and stability in a coordinated fashion in response to environmental and intracellular cues. Indeed, we know of regulatory proteins that bind transcripts encoding functionally related genes and switch between promoting decay or promoting translation in response to regulatory phosphorylation. We believe that this represents a more widespread model. The broad scientiﬁc goal of this proposal is to elucidate the functional networks of post- transcriptional regulation in the cell. We will apply high-throughput and unbiased approaches to work outward from mRNA-binding proteins in order to identify the signals that control their activity, the upstream and downstream factors that mediate their effect, and the regulatory programs that they control. Our work will reveal the general principles governing how and why gene expression is controlled post-transcriptionally. We will also develop approaches that can be transferred to address this question in a wide array of other biological systems.

抽象的细胞通过调节翻译和衰减来应对环境变化和压力细胞质中的mRNA。该转录后法规对于维持适当的条件至关重要细胞生理。通常，这些调节程序可以保护细胞免受病理应激。在然而，其他情况下，适应不良的反应是疾病表型的基础。理解这些动态，环境响应迅速的转录后监管计划至关重要了解细胞生理并承诺新型的治疗靶标以支持受保护响应并抑制破坏性的反应。最近的工作已经分类了数百种mRNA结合蛋白。我们对如何的理解这些蛋白质会影响它们结合的mRNA，落后于研究蛋白质，我们通常缺乏对它们在细胞中更广泛的作用的理解。我们的动力假设是，这些蛋白质中的许多靶向特定转录本并调节其翻译以及以环境和细胞内提示的方式以协调方式的稳定性。确实，我们知道结合编码功能相关基因的转录本的调节蛋白在促进衰减或促进翻译之间切换以响应调节磷酸化。我们认为，这代表了一个更广泛的模型。该提案的广泛科学目标是阐明后的功能网络细胞中的转录调节。我们将采用高通量和公正的方法从mRNA结合蛋白向外工作，以确定控制其控制的信号活动，介导其作用的上游和下游因素以及调节性他们控制的程序。我们的工作将揭示有关如何以及为什么的一般原则基因表达在转录后受到控制。我们还将开发可以转移以在其他各种生物系统中解决这个问题。