Metabolic and genetic interactions among mutans streptococci

变形链球菌之间的代谢和遗传相互作用

• 批准号: 9300540
• 负责人: Paul Anthony Jensen
• 金额: $ 11.03万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-02 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9300540
• 关键词: Acids; Antibiotics; Area; Bacteria; Bioinformatics; Biological Markers; Bypass; Carbon; Chemicals; Child; Clinical; Coculture Techniques; Collaborations; Communities; Competence; Computational Technique; Computer Simulation; Data; Data Set; Dental Prophylaxis; Dental caries; Disease; Drug Targeting; Environment; Enzymes; Gene Deletion; Gene Expression; Genes; Genetic; Genome; Genomics; Goals; Growth; Impairment; In Vitro; Individual; Knowledge; Left; Maps; Measures; Metabolic; Metabolism; Methods; Modeling; Molecular; Mono-S; Oral health; Outcome; Oxidases; Pathway interactions; Patients; Peroxides; Phenotype; Positioning Attribute; Preclinical Drug Evaluation; Process; Production; Publications; Rattus; Reader; Resistance; Route; Saliva; Salts; Sampling; Shapes; Source; Streptococcus; Streptococcus mutans; Stress; System; Testing; Tooth Demineralization; Work; acid stress; bacterial fitness; base; comparative; design; effective therapy; environmental change; experience; experimental study; fitness; follow-up; genetic manipulation; genetic profiling; genome analysis; genome-wide; in vivo; instrumentation; knockout gene; large scale simulation; metabolic phenotype; metabolomics; microbial community; new therapeutic target; novel; novel therapeutics; oral bacteria; oral streptococci; overexpression; personalized medicine; prevent; programs; quorum sensing; screening; simulation; sugar; therapeutic target; therapy design; tool; tooth surface; transcriptomics

Project Summary/Abstract Tooth decay (caries) is caused by acid produced primarily by the mutans streptococci, a group of bacteria that colonize the tooth surface. The namesake of the mutans streptococci, S. mutans, is widely studied for its detriments to oral health. Numerous publications have profiled the metabolism, competence, quorum sensing, and acid tolerance of S. mutans, both in vitro and in vivo. The genome of S. mutans is easily manipulated, facilitating our detailed knowledge of the bacterium's genetics. The other mutans streptococci, S. sobrinus, is not genetically facile and is understudied compared to S. mutans. Although S. sobrinus colonization occurs less frequently, its presence is associated with more aggressive caries, especially in children. S. sobrinus clinical isolates are better able to cause caries in rat models, and in vitro cultures of S. sobrinus can tolerate higher acid concentrations than S. mutans. The field's focus on S. mutans has left significant gaps in our knowledge of S. sobrinus, its mechanism of increased cariogenicity, and its interactions with S. mutans. This project aims to systematically expand our knowledge of the mutans streptococci through a combination of experimental and computational techniques. We will: 1) perform a comprehensive genomic, metabolomic, and phenotypic characterization of S. mutans, S. sobrinus, and their interactions; 2) develop genome-scale metabolic models of the bacteria to integrate the datasets and test hypotheses; and 3) experimentally map inter-species genetic interactions to validate and expand our models. Our data-driven, computational approach will enhance our understanding of the similarities and differences among the mutans streptococci. The ability to simulate gene knockouts, environmental changes, and chemical perturbations in silico helps overcome S. sobrinus' resistance to genetic manipulation. The simulations will also create a prioritized “short- list” of promising drug targets for follow-up experiments. Combining experiments and computation bypasses large, expensive wet-lab screens and provides a faster path to novel treatments for dental caries.

项目总结/摘要 蛀牙（龋齿）主要是由变形链球菌产生的酸引起的，变形链球菌是一组细菌， 定居在牙齿表面。变形链球菌S.变异体，被广泛研究， 注意口腔健康。许多出版物已经描述了新陈代谢，能力，群体感应， S.在体外和体内均存在。S.变异体很容易被操纵， 帮助我们更详细地了解细菌的遗传学。其它变形链球菌为S.索布里努斯群岛 遗传上不容易，与S相比研究不足。变异人虽然S. sobrinus殖民发生 在不太常见的情况下，它的存在与更严重的龋齿有关，尤其是在儿童中。S.远缘 临床分离物在大鼠模型中更能引起龋齿，并且S. sobrinus可以容忍 酸浓度高于S.变异人该领域的重点是S。变种人在我们的研究中留下了巨大的空白 S的知识。sobrinus，其增加致龋性的机制，以及其与S.变异人 本项目旨在通过以下方法系统地扩展我们对变异链球菌的认识： 实验和计算技术。我们将：1）进行全面的基因组学，代谢组学， S. mutans，S. sobrinus及其相互作用; 2）发展基因组规模 细菌的代谢模型，以整合数据集和测试假设;以及3）实验映射 物种间遗传相互作用来验证和扩展我们的模型。我们的数据驱动、计算 方法将加强我们对变形链球菌之间的相似性和差异的理解。 计算机模拟基因敲除、环境变化和化学扰动的能力有助于 克服S。sobrinus对基因操作的抵抗模拟还将创建一个优先的“短- 列出了有希望的药物靶点，供后续实验使用。结合实验和计算旁路 大型、昂贵的湿实验室筛选，并为龋齿的新型治疗提供了更快的途径。