Molecular Basis and Cellular Roles of Translational Regulation

翻译调控的分子基础和细胞作用

基本信息

批准号：
8755583
负责人：
NICHOLAS T INGOLIA
金额：
$ 235.38万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-30 至 2019-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Translational control of gene expression plays an essential role in diverse areas of biology, ranging from cellular stress responses to learning and memory. Despite the prevalence and importance of translational regulation, we have a limited view of the genes whose expression is affected and even less understanding of the ways in which their translation is controlled. In part, the study of translation has been limited by the relative difficulty of measuring it. I recently developed ribosome profiling as a technique to address this need for genome-wide, quantitative analysis of translation. Comprehensive and precise translational profiling has already proven its value by revealing novel expression regulation occurring in well-studied biological processes. Here, I propose to extend this exploration of translational control as an underappreciated component of cellular stress responses with direct relevance to human disease. While identifying regulated genes yields key insights into cellular physiology, it does not address directly the molecular basis of translationa control. The ultimate goal of my proposed research is to better explain the regulation of translation. Insights gained from such an understanding will impact many areas of biology, as translation is a fundamental process. They will also represent keys to enhancing or suppressing stress-induced gene expression programs in order to treat disease. I propose that translation is greatly affected by diverse mRNA-binding proteins that recognize sequence or structural elements encoded in the transcript. We now know that there are many hundreds of these mRNA-binding proteins, but their functional impact is not well understood. I will intersect global experimental maps of protein occupancy with translation profiling in order to link gene expression programs with regulatory factors and gain a better understanding of how translational regulation is specified. Finally, I propose that the mechanistic basis of translationl control can be understood through the identification and study of general coregulatory factors that are recruited to mRNAs by pathway-specific regulatory proteins. I will discover these coregulators based on their functional impact on expression and learn how they act, thereby revealing the specific molecular events that enhance or suppress translation. By intersecting expression, occupancy, and functional data sets, I will broaden our view of translational control single mRNAs to answer more generally one of the fundamental questions in how cells regulates protein abundance to control their physiology, allowing us to better understand the behaviors of healthy cells and intervene in disease.

描述（由申请人提供）：基因表达的翻译控制在生物学的不同领域起着至关重要的作用，范围从细胞压力反应到学习和记忆。尽管转化调节的普遍性和重要性，但我们对这些基因的表达受到影响，甚至对控制其翻译的方式的理解更少。在某种程度上，翻译的研究受到测量相对难度的限制。我最近开发了核糖体分析，作为解决对全基因组的这种需求的一种技术，对翻译的定量分析。全面而精确的翻译分析已经通过揭示在经过充分研究的生物学过程中发生的新表达调控来证明其价值。在这里，我建议将转化控制的探索扩展为细胞应激反应的不足部分，与人类疾病直接相关。在鉴定受调节的基因会产生对细胞生理学的关键见解，但它不能直接解决转化控制的分子基础。我提出的研究的最终目标是更好地解释翻译的调节。从这种理解中获得的见解将影响生物学的许多领域，因为翻译是一个基本过程。它们还将代表增强或抑制压力诱导的基因表达程序以治疗疾病的关键。我建议翻译受到多种mRNA结合蛋白的影响，这些蛋白质识别转录本中编码的序列或结构元素。我们现在知道，有数百种这样的mRNA结合蛋白，但是它们的功能影响尚未得到很好的理解。我将将蛋白质占用率的全球实验图与翻译分析相结合，以将基因表达程序与调节因素联系起来，并更好地了解如何指定翻译调节。最后，我建议可以通过鉴定和研究通过途径特异性调节蛋白募集到mRNA的一般核调节因子来理解翻译控制的机理基础。我将根据它们对表达的功能影响并了解它们的作用，从而揭示这些核心测量剂的作用，从而揭示增强或抑制翻译的特定分子事件。通过相交的表达，占用和功能数据集，我将扩大我们对翻译控制单个mRNA的看法，以回答更普遍的回答细胞如何调节蛋白质丰度以控制其生理学的基本问题之一，从而使我们能够更好地了解健康细胞的行为和疾病中的健康细胞的行为。