Physiologic state modulation by conditional translational complexes

条件翻译复合体调节生理状态

• 批准号: 1616955
• 负责人: Nitin Baliga
• 金额: $ 119.94万
• 依托单位: Institute for Systems Biology
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1616955&HistoricalAwards=false
• 关键词: Physiologic; state; modulation; conditional; translational

The process of gene expression, encompassing transcription and translation, is closely interconnected with cellular physiology, and is carried out by all organisms on Earth. Yet, the process of translation and its impact on cellular physiology is generally thought to be subordinate to transcriptional regulation and post-translational signaling. This notion continues despite the fact that both transcription and signaling depend on proteins, and hence on translation. This project seeks to identify a universal aspect of gene expression and physiology that has been overlooked. This project will test the novel idea that proteins needed under particular environmental conditions are preferentially translated when exposed to such conditions. The proposed studies may uncover a new molecular mechanism for gene regulation and will greatly advance our understanding of the unifying, central role of translation in controlling a myriad life processes. In addition, the project will contribute to training of K-12 students and teachers, and high school science curriculum development. The proposed research will address whether functional diversity of components of the translation system and their transcriptionally generated modular expression regulate large-scale physiological state transitions in organisms. The underlying hypothesis is that environment-dependent physiological cell states are generated by the conditional production, assembly, and activity of distinct ribosomal complexes with variable subunit compositions. This hypothesis is based on the intriguing organization of translational machinery genes within gene regulatory networks of phylogenetically diverse organisms. Specifically, ribosomal subunits and other translation system proteins are conditionally co-regulated as multiple distinct, yet overlapping modules with un-correlated expression patterns across environmental shifts. The proposed research will attempt to observe conditional association of certain ribosomal subunits, and whether this association directs the translation complex to preferentially translate transcripts encoding functions for a particular environment-relevant physiological state. Protein (using SWATH mass spectrometry) and mRNA (with RNA-seq) compositions of ribosomal complexes will be characterized across environmental shifts (e.g., aerobic to anaerobic) that effect large physiological state transitions. Additionally, the proposed research will predictably manipulate the physiological state of each organism by engineering environment-responsive regulation or knock outs of conditional ribosomal subunits. Altered regulation of specific conditionally expressed ribosomal subunits should manifest an inappropriate physiological state transition relative to the environmental shift. Generality of the hypothesis will be assessed by performing studies using model microorganisms from the three domains of life - H. salinarum (archaeon), E. coli (bacterium), and S. cerevisiae (eukaryote). These proposed activities will demonstrate whether variable translation complexes drive environment-dependent physiological transitions.

基因表达的过程，包括转录和翻译，与细胞生理学紧密相互联系，并由地球上的所有生物进行。然而，通常认为翻译过程及其对细胞生理的影响属于转录调控和翻译后信号传导。尽管转录和信号传导都取决于蛋白质，因此仍取决于翻译，这一概念仍在继续。该项目旨在确定被忽略的基因表达和生理学的普遍方面。 该项目将测试以下新想法，即在特定环境条件下需要蛋白质在暴露于此类条件时优先翻译。 拟议的研究可能会揭示一种用于基因调节的新分子机制，并将大大促进我们对翻译在控制众多寿命过程中统一的核心作用的理解。 此外，该项目将有助于培训K-12学生和教师以及高中科学课程的发展。 拟议的研究将解决翻译系统组成部分的功能多样性及其转录产生的模块化表达是否会调节生物体中的大规模生理状态过渡。潜在的假设是，与环境依赖性生理细胞态是由具有可变亚基组成的不同核糖体复合物的条件产生，组装和活性产生的。该假设基于在系统发育多样的生物体基因调节网络中的转化机械基因的有趣组织。具体而言，核糖体亚基和其他翻译系统蛋白在有条件地共同调节为多个不同但重叠的模块，并在环境变化之间具有无关的表达模式。拟议的研究将试图观察某些核糖体亚基的条件关联，以及该关联是否指导翻译复合体以优先翻译针对特定环境与环境相关的生理状态的转录本。蛋白质（使用质谱质谱法）和mRNA（带有RNA-seq）的核糖体复合物的组成将在环境变化（例如有氧对厌氧至厌氧）之间进行表征，从而影响较大的生理状态过渡。此外，拟议的研究将通过工程环境响应性调节或有条件的核糖体亚基的敲击来预测地操纵每种生物的生理状态。针对特定表达的核糖体亚基的调节改变应表现出相对于环境转移的不当生理状态转变。假设的一般性将通过使用来自生命的三个领域的模型微生物进行研究-H。salinarum（Archaeon），大肠杆菌（细菌）和S. cerevisiae（真核生物）。这些提出的活动将证明可变翻译复合物是否驱动环境依赖性生理转变。