Investigating Membrane Alterations as a Mechanism of Acid Tolerance in Cariogenic Bacteria

研究膜改变作为致龋细菌耐酸机制

基本信息

批准号：
10624648
负责人：
Jonathon Baker
金额：
$ 13.09万
依托单位：
J. CRAIG VENTER INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10624648
关键词：
Acids Address Attention Award Bacteria Caries prevention Cell membrane Chronic Communicable Diseases Complex Data Dental Enamel Dental caries Disease Ensure Environment Fluorides Funding Goals In Vitro Institutes Investigation Lactobacillus casei Mass Spectrum Analysis Mediating Membrane Mentors Microbial Biofilms Microbiology Modeling Modification Molecular Oral Pathogenesis Phase Prevalence Prevention strategy Research Research Training Scientist Streptococcus mutans Therapeutic Training Universities Unsaturated Fatty Acids Virulence acid stress anticaries bioinformatics tool biological adaptation to stress career development cariogenic bacteria combat community setting demineralization environmental stressor improved interest lectures lipidomics microbial novel novel therapeutics oral bacteria oral biofilm oral microbiome pathogen prevent programs response skills tooth surface

项目摘要

Project Summary/Abstract Dental caries is the most common chronic infectious disease globally and is caused by the formation of acid- producing bacterial biofilms on the tooth surface, which demineralize and destroy the protective underlying enamel barrier. Although the efficacy of fluoride treatments (the contemporary standard in caries prevention) is well-documented, the current prevalence of the disease clearly illustrates that fluoride alone is insufficient to prevent caries in many situations. Therefore, increased understanding of disease pathogenesis and exploration of novel preventative strategies are objectives worthy of attention. Regardless of the microbial taxa involved, bacterial acid-tolerance is an indispensable factor in caries pathogenesis. The known caries pathogen Streptococcus mutans increases the proportion of unsaturated fatty acids (UFAs) in its plasma membrane in response to environmental acidification—an adaptation required for acid-tolerance and virulence. Preliminary data indicates that several other Gram-positive oral taxa, including the caries-associated species, Lactobacillus casei, modify their membranes in a similar manner in response to environmental acidification. This proposal addresses a number of currently unanswered questions raised by these observations. Aims 1 and 2 of the proposed research will determine the scope of this response to acid stress across the oral microbiome, in single taxa or in a community setting. Aim 3 of this proposal will elucidate how these UFAs are protective against acid- mediated damage. These aims will be accomplished using bioinformatics tools, basic molecular microbiology, an ecologically-relevant and complex in vitro oral biofilm model, and mass spectrometry/lipidomics. Successful completion of the proposed research will answer pertinent questions regarding caries pathogenesis in a multi- species setting and is likely to open the door to investigation of novel anti-caries therapeutics which, while targeting acidophiles, function regardless of the presence and abundance of S. mutans. The candidate, Dr. Jonathon Baker, has a longstanding interest in the microbiology of dental caries. Upon completion of the K99 (mentored) phase of this award, his goal is to become an independent PI at a leading research university, where he plans to continue research on the modifications that bacteria make to their membranes to combat environmental stresses, while leveraging acquired data to develop novel therapeutics. A funded K99/R00 proposal will allow Dr. Baker to develop skills necessary to both complete the proposed research (training in mass spectrometry/lipidomics) and subsequently become an independent research scientist (training in didactic lecturing, mentoring, and grantsmanship). Dr. Baker’s mentors, Drs. Victor Nizet and Pieter Dorrestein, and environment (J. Craig Venter Institute and UC San Diego) have been carefully selected to provide high-quality, diverse scientific and collegial support, as well as state-of-the-art facilities, to ensure successful completion of this research program and the proposed career development goals.

项目概要/摘要龋齿是全球最常见的慢性传染病，是由酸的形成引起的在牙齿表面产生细菌生物膜，使牙齿底层脱矿质并破坏保护层尽管氟化物治疗（预防龋齿的当代标准）的功效是有限的。有据可查，目前该疾病的流行清楚地表明，仅靠氟化物不足以治愈因此，预防龋齿的情况很多。无论涉及哪些微生物类群，新的预防策略都是值得关注的目标。细菌耐酸是龋齿发病机制中不可缺少的因素。变形链球菌增加其质膜中不饱和脂肪酸（UFA）的比例对环境酸化的反应——耐酸和毒力所需的适应。数据表明，其他几种革兰氏阳性口腔分类群，包括与龋齿相关的物种，乳酸菌干酪，以类似的方式修改其膜以应对环境酸化。解决了这些观察的目标 1 和 2 提出的一些目前尚未解答的问题。拟议的研究将确定整个口腔微生物组对酸应激的这种反应的范围，在单一的该提案的目标 3 将阐明这些 UFA 如何防止酸- 这些目标将通过生物信息学工具、基础分子微生物学来实现。生态相关且复杂的体外口腔生物膜模型，以及质谱/脂质组学成功。完成拟议的研究将回答有关多方面龋齿发病机制的相关问题物种设置，并可能为研究新型抗龋齿疗法打开大门，同时无论变异链球菌是否存在和丰度如何，都可以针对嗜酸菌发挥作用。 Jonathon Baker 在完成 K99 后对龋齿微生物学有着长期的兴趣。在该奖项的（指导）阶段，他的目标是成为一所领先研究型大学的独立 PI，其中他计划继续研究细菌对其膜进行的修饰以对抗环境压力，同时利用获得的数据开发新的疗法。提案将使贝克博士能够发展必要的技能来完成拟议的研究（培训质谱/脂质组学），随后成为一名独立研究科学家（接受教学培训贝克博士的导师 Victor Nizet 博士和 Pieter Dorrestein 博士以及环境（J.克雷格文特尔研究所和加州大学圣地亚哥分校）经过精心挑选，以提供高质量、多样化的科学和大学支持以及最先进的设施，以确保成功完成本研究计划和拟议的职业发展目标。