Regulation and Physiological Roles of Translational Fidelity

翻译保真度的调节和生理作用

• 批准号: 10406906
• 负责人: JIQIANG LING
• 金额: $ 38.23万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10406906
• 关键词: Affect; Amino Acids; Antibiotics; Bacteria; Behavior; Cells; Cues; Defect; Development; Escherichia coli; Genes; Genetic; Genetic Translation; Growth; Hospitalization; Impairment; Individual; Laboratories; Lead; Mammals; Messenger RNA; Multiple Bacterial Drug Resistance; Nerve Degeneration; Pathway interactions; Physiological; Population; Process; Protein Biosynthesis; Proteins; Quality Control; Regulation; Reporter; Research; Role; Salmonella; Salmonella enterica; Stress; System; Terminator Codon; United States; Virulence; Work; antimicrobial; cell motility; environmental change; fitness; genetic information; improved; insight; interest; new technology; novel; pathogenic bacteria; response

PROJECT SUMMARY Accurate translation of the genetic information from messenger RNA to protein depends on multiple quality control mechanisms, which collectively maintain the average levels of translational errors at 10-4 for amino acid misincorporation (missense errors) and 10-2 for stop codon readthrough. However, increasing evidence shows that such translational fidelity is not fixed, but is rather affected by various environmental cues and genetic factors. Currently, we are only beginning to understand the regulatory networks leading to the fluctuation of translational fidelity during environmental changes and the resulting physiological responses. Translational errors can lead to reduced fitness, such as growth defects in bacteria and neurodegeneration in mammals, but may also benefit cells under certain stress conditions. Recently, we have shown that translational error rates vary from cell to cell in a genetically-identical bacterial population, raising the interesting question as to how fluctuation of translational errors affects the behavior of individual cells. In my laboratory, we are interested in developing and applying new technologies to understand the regulation and physiological roles of translational fidelity at both the population and single-cell levels. We are using our recently developed high-throughput reporter system to screen for conditions that alter translational fidelity, and have already identified novel environmental and genetic factors that are critical for this process. Next, we will determine the underlying mechanisms and expand our screens. Another research direction is to study how translational fidelity affects bacteria-host interactions, which is poorly understood. Our recent work reveals that either decreasing or increasing translational fidelity impairs expression of virulence genes and motility in Salmonella, suggesting that an optimal level of translational errors benefit bacteria during host interactions. We will further determine the regulatory networks using population and single- cell approaches. These studies will provide important insights into the roles of translational fidelity in environmental adaption and the regulatory mechanisms.

项目摘要 从信使RNA到蛋白质的遗传信息的准确翻译取决于多种质量 控制机制，该机制共同维持氨基酸的平均平移误差水平为10-4 终止密码子读取的误导（错义错误）和10-2。但是，越来越多的证据表明 这种翻译保真度不是固定的，而是受各种环境线索和遗传因素的影响。 目前，我们才开始了解导致翻译波动的监管网络 环境变化和由此产生的生理反应期间的保真度。翻译错误可能导致 适应性降低，例如细菌的生长缺陷和哺乳动物的神经退行性，但也可能受益 在某些应力条件下细胞。最近，我们表明翻译错误率因细胞而异 在遗传性的细菌种群中，提出了一个有趣的问题，即转化如何波动 错误会影响单个细胞的行为。在我的实验室中，我们有兴趣开发和应用新的 了解转化忠诚度在两个人群中的调节和生理作用的技术 和单细胞水平。我们正在使用最近开发的高通量记者系统来筛选 改变翻译保真度并已经确定了新的环境和遗传因素的条件 这对于此过程至关重要。接下来，我们将确定基本机制并扩展我们的屏幕。 另一个研究方向是研究转化忠诚如何影响细菌 - 宿主相互作用，这是很差的 理解。我们最近的工作表明，减少或增加的翻译保真度会损害表达 沙门氏菌中的毒力基因和运动性，这表明最佳的翻译错误有益 宿主相互作用期间的细菌。我们将进一步确定使用人群和单一的监管网络 细胞方法。这些研究将为转化忠诚中的作用提供重要的见解 环境适应和监管机制。