Molecular Basis and Cellular Roles of Translational Regulation

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重要作用，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，我们有一个有限的看法，其表达受到影响的基因，甚至更少的了解，其中他们的翻译是控制。翻译的研究在一定程度上受到了测量难度的限制，我最近开发了核糖体分析技术，以满足全基因组翻译定量分析的需求。全面和精确的翻译谱已经证明了它的价值，揭示了新的表达调控发生在充分研究的生物过程。在这里，我建议扩展这种探索的翻译控制作为一个未被充分重视的组成部分，细胞应激反应与人类疾病的直接相关性。虽然确定受调控的基因产生细胞生理学的关键见解，但它并没有直接解决代谢控制的分子基础。我所提出的研究的最终目标是更好地解释翻译的规则。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。它们也将代表增强或抑制应激诱导的基因表达程序以治疗疾病的关键。我认为翻译受到不同的mRNA结合蛋白的很大影响，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，但它们的功能影响还不清楚。我将交叉全球蛋白质占用的实验地图与翻译分析，以连接基因表达程序与调控因子，并获得更好的理解如何翻译调控指定。最后，我建议，通过识别和研究由途径特异性调节蛋白招募到mRNA的一般共调节因子，可以理解抑制控制的机制基础。我将发现这些辅助调节因子的基础上，他们的功能表达的影响，并了解他们如何发挥作用，从而揭示特定的分子事件，增强或抑制翻译。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mRNA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学的基本问题之一，使我们能够更好地了解健康细胞的行为并干预疾病。

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.