Molecular Basis and Cellular Roles of Translational Regulation

描述（申请人提供）：基因表达的翻译控制在生物学的各个领域起着至关重要的作用，从细胞应激反应到学习和记忆。尽管翻译调控的普遍性和重要性，但我们对其表达受影响的基因的看法有限，对其翻译受控制的方式的了解更少。在某种程度上，翻译的研究受到了相对难以衡量的限制。我最近开发了核糖体分析作为一种技术来解决全基因组翻译定量分析的需求。全面和精确的翻译分析已经通过揭示在充分研究的生物过程中发生的新的表达调控证明了它的价值。在这里，我建议扩展翻译控制的探索，作为与人类疾病直接相关的细胞应激反应的一个未被充分认识的组成部分。虽然鉴定受调控的基因对细胞生理学产生了关键的见解，但它并不能直接解决翻译控制的分子基础。我所提出的研究的最终目的是为了更好地解释翻译的规律。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多种mrna结合蛋白的影响，这些蛋白可以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，但它们的功能影响还不太清楚。我将把蛋白质占用的全球实验图与翻译分析相结合，以便将基因表达程序与调节因子联系起来，并更好地理解如何指定翻译调节。最后，我提出翻译控制的机制基础可以通过识别和研究通过途径特异性调节蛋白募集到mrna的一般协同调节因子来理解。我将根据它们对表达的功能影响来发现这些共调节因子，并了解它们是如何起作用的，从而揭示增强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mrna的看法，以更广泛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，使我们能够更好地理解健康细胞的行为并干预疾病。

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.