Investigating Mechanisms of Fluoride Sensing and Toxicity Mitigation in Bacteria

描述（由申请人提供）：核糖开关是结构化的RNA结构域，通常位于信使RNA的52个非翻译区（UTR）中，它们选择性地结合靶代谢物并调节基因表达。我们已经发现了一个氟化物响应核糖开关类，它提供了一个前所未有的机会，建立氟化物毒性的分子基础，并减轻分布在两个生物体中的氟化物毒性。 人生的三个领域特别令人感兴趣的是来自细菌物种的氟化物核糖开关的研究，因为这可能对理解水和牙齿卫生产品中氟化物添加剂的健康影响产生影响。我们试图提供一个强大的生化和遗传基础，以了解氟离子是如何被许多物种感知的，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支持，以阐明氟化物毒性、抗龋齿功效和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，以发现更多的氟化物敏感RNA，研究已知和新发现的氟化物核糖开关的生物化学和遗传功能，并研究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存在的假设，即氟化物的抗菌活性有助于预防龋齿。 公共卫生相关性：氟化物因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。在所提出的氟化物作用机制中，有一种是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的氟化物传感系统，为理解和利用细菌中的氟化物毒性提供了非凡的机会。

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.