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控制mRNA翻译和衰变的动态分子网络的功能基因组学

已有 1843 次阅读 2019-3-12 22:12 |系统分类:科研笔记

NICHOLAS T INGOLIA (2019-03-01 to 2023-02-28) Functional genomics of the dynamic molecular network controlling mRNA translation and decay. Amount: $305401

控制mRNA翻译和衰变的动态分子网络的功能基因组学

Abstract

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 speci?c 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 scienti?c 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.

摘要细胞通过调节胞质溶胶中mRNA的翻译和衰变来响应环境变化和应激。这种转录后调节对于维持适当的细胞生理学至关重要。通常,这些监管计划保护细胞免受病理应激。然而,在其他情况下,适应不良反应是疾病表型的基础。了解这些动态的,环境响应的转录后调控程序对于理解细胞生理学至关重要,并承诺新的治疗靶点以支持保护性反应并抑制有害的反应。最近的工作已经编目了数百种mRNA结合蛋白。我们对这些蛋白质如何影响它们结合的mRNA的理解落后于列举这些蛋白质的研究,我们通常缺乏对它们在细胞中更广泛作用的理解。我们的激励假设是,许多这些蛋白质针对特定的转录物并以协调的方式调节它们的翻译和稳定性以响应环境和细胞内线索。实际上,我们知道结合编码功能相关基因的转录物的调节蛋白,并在响应调节磷酸化促进衰变或促进翻译之间切换。我们认为这代表了一种更为普遍的模式。该提议的广泛科学目标是阐明细胞中转录后调控的功能网络。我们将应用高通量和无偏差的方法从mRNA结合蛋白向外工作,以确定控制其活性的信号,调节其作用的上游和下游因素,以及它们控制的监管程序。我们的工作将揭示控制转录后基因表达如何以及为何受到控制的一般原则。我们还将开发可以转移的方法,以在许多其他生物系统中解决这个问题。

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