Bacterial ribosome heterogeneity and gene expression

细菌核糖体异质性和基因表达

• 批准号: 10713812
• 负责人: Kathryn Mary Ramsey
• 金额: $ 37.5万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713812
• 关键词: Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Award; Bacterial Infections; Cells; Development; Drug Targeting; Funding; Future; Gene Expression; Goals; Heterogeneity; Homologous Gene; Knowledge; Laboratories; Organism; Production; Public Health; Research; Ribosomal Proteins; Ribosomes; Source; Technology; Translations; United States; Virulence Factors; Work; antimicrobial; antimicrobial drug; bacterial genetics; combat; design; drug efficacy; functional outcomes; improved; inhibitor; innovation; insight; novel; novel therapeutics; pathogenic bacteria; programs; virulence gene

PROJECT SUMMARY As antibiotic resistance increases globally, there is an urgent need for new drugs to combat bacterial infections. Approaches to developing new antimicrobials include inhibiting essential steps in gene expression and inhibiting virulence factor production. The overarching focus of the research program in my laboratory is to understand how bacterial cells regulate gene expression, to ultimately identify novel targets for antimicrobial development. The research funded by this award will leverage the Ramsey laboratory’s expertise in bacterial genetics and state of the art technologies to examine the impacts of ribosome heterogeneity in multiple bacterial species. The Ramsey laboratory identified a specific homolog of the ribosomal protein bS21 that governs virulence gene expression in a bacterial pathogen. These findings suggest that heterogeneity in ribosomes, which are significant drug targets, can lead to changes in gene expression. The impacts of ribosome heterogeneity on translation, gene expression, and drug efficacy are generally not well understood and represent key gaps in our knowledge. Over the next five years, we propose to continue our studies to understand the effects of ribosome heterogeneity on multiple bacterial species. The proposed work is innovative because it takes a rigorous, reductionist approach to examine one poorly- understood source of ribosome heterogeneity with species-specific impacts on translation to elucidate fundamental features of translation and inform the design of novel antimicrobials. Our goals include determining how multiple bS21 homologs function to govern gene expression, why bS21 is essential in some cells, and how bS21 contributes to antibiotic sensitivity. We expect our work will allow us to make clear connections between ribosome composition and functional outcomes, as we will limit the complexity of ribosomal heterogeneity to changes in a single ribosomal protein, bS21. Expected future work will include developing screens for novel, specific ribosome inhibitors and studying the function of bS21 or other independent sources of ribosome heterogeneity in these and/or other organisms. Ultimately our studies will provide key insights into ribosome function, gene expression, and may identify novel targets for antimicrobial drugs.

项目概要 随着全球抗生素耐药性的增加，迫切需要新药 对抗细菌感染的方法包括抑制。 基因表达和抑制毒力因子产生的重要步骤。 我实验室研究项目的重点是了解细菌细胞如何 调节基因表达，最终确定抗菌药物的新靶点 该奖项资助的研究将利用拉姆齐实验室的开发。 细菌遗传学方面的专业知识和最先进的技术来检查细菌的影响 拉姆齐实验室发现了多种细菌物种的核糖体异质性。 核糖体蛋白 bS21 的特定同源物，控制毒力基因的表达 这些发现表明核糖体存在显着的异质性。 药物靶点，可导致基因表达的变化，核糖体异质性的影响。 翻译、基因表达和药物功效通常没有被很好地理解和代表 在接下来的五年里，我们建议继续研究以弥补我们知识上的关键差距。 了解核糖体异质性对多种细菌物种的影响。 工作是创新的，因为它需要一种严格的、还原论的方法来检验一个糟糕的—— 了解核糖体异质性的来源及其对翻译的物种特异性影响 阐明翻译的基本特征并为新型抗菌药物的设计提供信息。 目标包括确定多个 bS21 同源物如何发挥作用来控制基因表达，为什么 bS21 在某些细胞中至关重要，以及 bS21 如何促进抗生素敏感性。 工作将使我们能够在核糖体组成和功能之间建立清晰的联系 结果，因为我们将核糖体异质性的复杂性限制为单个变化 核糖体蛋白，bS21 预计未来的工作将包括开发新颖的、特异性的筛选。 核糖体抑制剂并研究 bS21 或其他独立核糖体来源的功能 最终，我们的研究将为了解这些和/或其他生物体的异质性提供重要见解。 核糖体功能、基因表达，并可能确定抗菌药物的新靶点。