Investigating Mechanisms of Fluoride Sensing and Toxicity Mitigation in Bacteria

研究细菌中氟化物传感和毒性减轻的机制

• 批准号: 8330504
• 负责人: RONALD R BREAKER
• 金额: $ 37.35万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-13 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8330504
• 关键词: Affinity; Animal Model; Anions; Anti-Bacterial Agents; Bacteria; Binding; Biochemical; Biochemical Genetics; Bioinformatics; Biological Assay; Caries prevention; Cells; Collection; Consensus; Culture Media; Data; Dental Hygiene; Dental Plaque; Dental caries; Distress; Elements; Emerging Technologies; Escherichia coli; Fluoride Ion; Fluorides; Foundations; Future; Gene Expression; Genes; Genetic; Goals; Health; Homologous Gene; Ions; Kinetics; Knowledge; Life; Mediating; Messenger RNA; Modeling; Molecular; Organism; Physiological; Polymers; Proteins; RNA; Research Personnel; Sensory; Streptococcus mutans; Structure; System; Testing; Toxic effect; Untranslated Regions; Water; aptamer; base; design; drinking water; empowered; genetic analysis; in vivo; insight; interest; member; microorganism; mutant; novel; prevent; protein function; research study; response; synthetic biology; tool; transcription termination

DESCRIPTION (provided by applicant): Riboswitches are structured RNA domains commonly located in the 52 untranslated regions (UTRs) of messenger RNAs where they selectively bind target metabolites and regulate gene expression. We have discovered a fluoride-responsive riboswitch class which offers an unprecedented opportunity to establish the molecular basis for fluoride toxicity and its alleviation in organisms distributed among two of the three domains of life. Of particular interest is the study of fluoride riboswitches from bacterial species because of the likely implications for understanding the health effects of fluoride additives in water and dental hygiene products. We seek to provide a strong biochemical and genetic foundation for understanding how fluoride ions are sensed by many species and what genetic consequences occur when cells detect dangerous levels of this anion. Moreover, our experiments are designed to produce data that empowers other researchers who wish to conduct studies that elucidate the molecular basis of fluoride toxicity, anti-caries efficacy, and bacterial responses to fluoride exposure. We will conduct bioinformatics searches to discover additional fluoride- sensing RNAs, examine the biochemical and genetic functions of known and new-found fluoride riboswitches, and examine the function of gene products whose expression is regulated by fluoride. This knowledge will help assess the long-standing hypothesis that the antibacterial activity of fluoride contributes to the prevention of dental caries. PUBLIC HEALTH RELEVANCE: Fluoride is widely used as an additive to drinking water and oral hygiene products due to its efficacy in preventing tooth decay. Among the proposed mechanisms of fluoride action is its antibacterial activity at high concentrations in dental plaque We have discovered a novel fluoride sensing system in microorganisms that provides extraordinary opportunities to understand and exploit fluoride toxicity in bacteria.

描述（由申请人提供）：核糖开关是结构化 RNA 结构域，通常位于信使 RNA 的 52 个非翻译区 (UTR)，在那里它们选择性地结合目标代谢物并调节基因表达。我们发现了一种氟化物响应性核糖开关类，它提供了前所未有的机会来建立氟化物毒性的分子基础及其在分布于两种生物体中的减轻作用。 生活的三个领域。特别令人感兴趣的是对细菌物种的氟化物核糖开关的研究，因为这可能对了解水和牙齿卫生产品中氟化物添加剂对健康的影响产生影响。我们寻求提供强大的生化和遗传基础，以了解许多物种如何感知氟离子，以及当细胞检测到这种阴离子的危险水平时会发生什么遗传后果。 此外，我们的实验旨在产生数据，为其他希望进行研究的研究人员提供帮助，以阐明氟化物毒性、抗龋齿功效以及细菌对氟化物暴露的反应的分子基础。我们将进行生物信息学搜索以发现其他氟化物感应RNA，检查已知和新发现的氟化物核糖开关的生化和遗传功能，并检查其表达受氟化物调节的基因产物的功能。这些知识将有助于评估长期以来的假设，即氟化物的抗菌活性有助于预防龋齿。 公众健康相关性：氟化物由于其预防蛀牙的功效而被广泛用作饮用水和口腔卫生产品的添加剂。所提出的氟化物作用机制之一是其在牙菌斑中高浓度时的抗菌活性。我们在微生物中发现了一种新型氟化物传感系统，为了解和利用细菌中氟化物的毒性提供了绝佳的机会。