Posttranscriptional regulation of gene expression in eukaryotes

真核生物基因表达的转录后调控

• 批准号: 7828752
• 负责人: KARSTEN WEIS
• 金额: $ 49.15万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7828752
• 关键词: Address; Affect; Amino Acids; Area; Biological Assay; Cell Death; Cell physiology; Cells; Classification; Code; Defect; Development; Disease; Environment; Eukaryota; Eukaryotic Cell; Event; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genetic Translation; Genome; Growth; Half-Life; Individual; Label; Laboratories; Life; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Measurement; Measures; Mediating; Messenger RNA; Methods; Molecular; Monitor; Nucleotides; Pathway interactions; Pattern; Physiologic pulse; Play; Post-Transcriptional Regulation; Process; Production; Proteins; Proteome; RNA; RNA Sequences; Regulation; Role; Running; Stable Isotope Labeling; System; Technology; Time; Transcriptional Regulation; Translations; acute stress; biological research; cell growth; cell type; human disease; insight; mRNA Decay; mRNA Stability; molecular dynamics; novel; prevent; programs; protein degradation; public health relevance; research study; response

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (06) Enabling Technologies and specific Challenge Topic, 06-GM-112: Molecular and Cellular Dynamics Technologies. A central problem in biological research is to understand how the genome is interpreted to determine the large diversity of organismal form and function. In addition, it is critical to identify misregulations that can occur during the interpretation of the genetic information in order to dissect and prevent the development of human diseases. While it has been well established that many important steps in the regulation of gene expression occur at the level of transcription, it has become increasingly clear that posttranscriptional processing is also essential for the precise control of gene expression in eukaryotic cells. Examples include the discovery of RNA-mediated silencing pathways that control mRNA translation or decay and play critical roles during organismal development or during the development of diseases such as cancer. However, in contrast to our excellent understanding of transcriptional control mechanisms, very little is still known about post-transcriptional regulatory programs. This is in part due to the lack of technologies that would enable us to analyze post-transcriptional control steps in a dynamic and non-invasive fashion. In this application, we will address this challenge and propose the development and application of novel labeling methods that will allow us to measure on a system-wide level the turnover of individual RNAs and proteins with high sensitivity and without perturbation of the cellular environment. For the first time, this will allow us to integrate changes that occur in transcription with measurements of mRNA stability, translation and protein turnover. Together, this will allow us to develop a comprehensive overview of the regulation of gene expression under various growth conditions and in different cell types. In the long run, my laboratory will explore new paradigms that emerge from these studies and will elucidate the molecular mechanism underlying novel regulatory responses. These studies will provide critical insight into the fundamental principles that determine the cellular dynamics of gene expression patterns and help us to understand defects that occur in human diseases. PUBLIC HEALTH RELEVANCE: In all eukaryotes, the tight regulation of gene expression is essential for cells to control proliferation, differentiation or development, and errors in any step of the gene expression program can have severe consequences leading to cell death or disease. A critical step in the control of gene expression is the control of mRNA and protein abundance by the regulation of their decay. Therefore, a better understanding of the regulation of mRNA and protein turnover is essential both for the understanding of fundamental cellular processes and the development of novel therapies for human diseases.

描述（由申请人提供）：本申请涉及广泛的挑战领域（06）使能技术和特定的挑战主题，06-GM-112：分子和细胞动力学技术。生物学研究的一个中心问题是理解基因组是如何被解释以决定生物体形式和功能的巨大多样性的。此外，必须查明在解释遗传信息期间可能发生的错误调节，以便剖析和预防人类疾病的发展。虽然已经确定基因表达调控中的许多重要步骤发生在转录水平，但越来越清楚的是，转录后加工对于真核细胞中基因表达的精确控制也是必不可少的。例如，发现了RNA介导的沉默途径，该途径控制mRNA的翻译或衰变，并在生物体发育或癌症等疾病的发展过程中发挥关键作用。然而，与我们对转录调控机制的深刻理解相反，我们对转录后调控程序知之甚少。这在一定程度上是由于缺乏技术，使我们能够分析转录后控制步骤的动态和非侵入性的方式。在本申请中，我们将解决这一挑战，并提出新的标记方法的开发和应用，使我们能够在系统范围内测量单个RNA和蛋白质的周转率，具有高灵敏度，并且不会干扰细胞环境。这将首次使我们能够将转录中发生的变化与mRNA稳定性，翻译和蛋白质周转的测量相结合。总之，这将使我们能够全面概述在各种生长条件下和不同细胞类型中基因表达的调控。从长远来看，我的实验室将探索从这些研究中出现的新范式，并阐明新的调控反应的分子机制。这些研究将为决定基因表达模式的细胞动力学的基本原理提供重要的见解，并帮助我们了解人类疾病中发生的缺陷。 公共卫生相关性：在所有真核生物中，基因表达的严格调控对于细胞控制增殖、分化或发育是必不可少的，并且基因表达程序的任何步骤中的错误都可能具有导致细胞死亡或疾病的严重后果。控制基因表达的一个关键步骤是通过调节mRNA和蛋白质的衰变来控制它们的丰度。因此，更好地理解mRNA和蛋白质周转的调节对于理解基本细胞过程和开发人类疾病的新疗法都是至关重要的。