Pyruvate oxidase: a molecular determinant of commensalism among the oral microbiome

丙酮酸氧化酶：口腔微生物群共生的分子决定因素

• 批准号: 10362734
• 负责人: Jens Kreth
• 金额: $ 49.83万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10362734
• 关键词: Acids; Actinomyces naeslundii; Aerobic; American Dental Association; Area; Biological Markers; Carbohydrates; Caries prevention; Clinical; Communities; Complex; Dental Plaque; Dental caries; Detection; Development; Diagnostic; Dietary Carbohydrates; Disease; Early Intervention; Environment; Enzymes; Fermentation; Goals; Growth; Guidelines; Health; Health Promotion; Hydrogels; Hydrogen Peroxide; In Vitro; Knowledge; Lead; Measurement; Measures; Metabolic; Methods; Microbial Biofilms; Microscopy; Molecular; Monitor; Mouth Diseases; Nature; Oral; Oral Microbiology; Oral health; Patients; Population; Post-Translational Protein Processing; Prevalence; Prevention; Process; Production; Pyruvate Oxidase; Regulation; Research; Resistance; Risk; Risk Assessment; Role; Sampling; Scanning; Streptococcus; Streptococcus mutans; Symbiosis; Techniques; Testing; Time; Tooth structure; Transcriptional Regulation; base; diagnostic accuracy; disorder prevention; dysbiosis; experience; feeding; improved; in vivo; innovation; insight; microbial; molecular marker; mouse model; oral biofilm; oral commensal; oral microbiome; oral streptococci; pathogen; polymicrobial disease; pre-clinical; prevent; protein protein interaction; response; sensor; success; systematic review; temporal measurement; tooth surface; trait

Project Summary Caries is one of the most prevalent oral diseases. Despite several decades of substantial caries research, only incremental progress has been made in disease prevention. Caries is the result of polymicrobial dysbiosis and not curable since the tooth structure is destroyed by fermentative acid by-products from caries-associated bacterial species. Therefore, strong emphasis should be on caries prevention. Caries risk assessment (CRA) is a widely accepted approach to caries prevention, but has been criticized because it leads to patients with increased risk not being identified. One drawback of CRA is that the polymicrobial nature of caries is not considered. Furthermore, it lacks any molecular markers sampled directly at the tooth surface where caries occurs. A key to improved CRA and prevention is a better understanding of molecular mechanisms that promote oral commensals associated with general oral health. We have identified an important trait of commensal oral streptococci that promotes molecular commensalism: the pyruvate oxidase, SpxB, provides a growth advantage under aerobic conditions since its metabolic activity generates additional ATP as well as pathogen-inhibiting H2O2. SpxB therefore enables early commensal streptococci to outgrow and inhibit H2O2 susceptible and caries-associated species. Our hypothesis is that commensal streptococci producing higher amounts of metabolically important ATP and inhibitory H2O2 are more competitive and thus allow dental plaque to be more resistant to cariogenic dysbiosis. We therefore propose the following Specific Aims: Aim 1: Cellular context - molecular mechanisms determining differential H2O2 production. Aim 2: Oral context - determine whether spxB regulation influences competitiveness in vivo. Aim 3: Clinical context - Real time measurements of H2O2 production and spxB expression from ex vivo dental plaques. The proposed aims will support our overall goal to better understand the health-associated traits of oral commensals and lead to a paradigm shift in caries research towards that of molecular commensalism; a vastly understudied area of oral microbiology. The gained knowledge will provide important new insight into the development of new strategies to prevent oral diseases like caries.

项目概要 龋齿是最常见的口腔疾病之一。尽管存在数十年的严重龋齿 研究表明，疾病预防方面仅取得了渐进性进展。龋齿的结果是 多种微生物失调且无法治愈，因为牙齿结构被发酵酸破坏 与龋齿相关的细菌物种的副产品。因此，应高度重视 预防龋齿。龋齿风险评估（CRA）是一种广泛接受的龋齿方法 预防，但受到批评，因为它导致风险增加的患者得不到治疗 确定。 CRA 的一个缺点是没有考虑龋齿的多种微生物性质。 此外，它缺乏直接在龋齿所在的牙齿表面取样的任何分子标记。 发生。改善 CRA 和预防的关键是更好地了解分子 促进与一般口腔健康相关的口腔共生的机制。我们有 确定了共生口腔链球菌的一个重要特征，可促进分子 共生现象：丙酮酸氧化酶 SpxB 在有氧条件下提供生长优势 因为它的代谢活动会产生额外的 ATP 以及病原体抑制作用 双氧水。因此，SpxB 能够使早期共生链球菌生长并抑制 H2O2 敏感物种和与龋齿相关的物种。我们的假设是共生链球菌 产生更多对代谢重要的 ATP 和抑制性 H2O2 竞争性，从而使牙菌斑对致龋性生态失调具有更强的抵抗力。我们 因此提出以下具体目标： 目标 1：细胞背景 - 决定 H2O2 产生差异的分子机制。 目标 2：口腔环境 - 确定 spxB 调节是否影响体内竞争力。 目标 3：临床背景 - 实时测量 H2O2 产生和 spxB 表达 来自离体牙菌斑。 拟议的目标将支持我们更好地了解与健康相关的特征的总体目标 口腔共生体的研究，并导致龋齿研究范式转向分子研究 共栖主义；口腔微生物学中一个未被充分研究的领域。所获得的 知识将为制定新战略提供重要的新见解，以防止 口腔疾病，如龋齿。