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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(申请人提供)：基因表达的翻译控制在生物学的不同领域中扮演着重要的角色，从细胞应激反应到学习和记忆。尽管翻译调控的流行和重要性，但我们对其表达受到影响的基因的看法有限，对其翻译控制的方式更是知之甚少。在某种程度上，翻译的研究受到了衡量翻译的相对困难的限制。我最近开发了核糖体图谱作为一种技术，以满足全基因组、定量分析翻译的需要。全面而精确的翻译图谱已经通过揭示发生在已被充分研究的生物过程中的新的表达调控而证明了其价值。在这里，我建议将翻译控制的探索扩展为与人类疾病直接相关的细胞应激反应中一个未得到充分认识的组成部分。虽然识别受调控的基因可以获得对细胞生理学的关键见解，但它并不直接涉及翻译的分子基础。我提出的研究的最终目的是为了更好地解释翻译的规则。从这样的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的过程。它们也将是增强或抑制压力诱导的基因表达程序以治疗疾病的关键。我认为翻译很大程度上受到不同的mRNA结合蛋白的影响，这些蛋白识别转录本中编码的序列或结构元件。我们现在知道有数百种这样的mRNA结合蛋白，但对它们的功能影响还不太清楚。我将把蛋白质占有率的全球实验图谱与翻译图谱交叉，以便将基因表达计划与调控因素联系起来，并更好地理解翻译调控是如何指定的。最后，我认为翻译控制的机制基础可以通过鉴定和研究一般的共调节因子来理解，这些共同调节因子是由途径特异的调节蛋白招募到mRNAs的。我将根据它们对表达的功能影响来发现这些协同调控因子，并了解它们是如何发挥作用的，从而揭示促进或抑制翻译的特定分子事件。通过交叉表达、占用和功能数据集，我将拓宽我们对翻译控制单个mRNAs的看法，以更普遍地回答细胞如何调节蛋白质丰度以控制其生理的基本问题之一，使我们能够更好地了解健康细胞的行为并干预疾病。