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.

项目摘要/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，破坏了保护性的底层搪瓷屏障。尽管氟化物治疗的效率（当代预防龋齿标准）是有据可查的疾病的当前患病率清楚地表明，仅氟化物不足以使在许多情况下预防汽车。因此，对疾病发病机理和探索的了解增加了新颖的预防策略是值得关注的目标。不管涉及的微生物类群如何细菌酸耐受性是汽车发病机理中必不可少的因素。已知的汽车病原体链球菌突变增加了其质膜中不饱和脂肪酸（UFAS）的比例对环境酸化的反应 - 耐酸和病毒所需的适应性。初步的数据表明，其他几个革兰氏阳性的口服分类单元，包括龋齿相关物种，乳酸杆菌 Casei，以相似的方式修改其机制，以响应环境酸化。这个建议解决了这些观察结果提出的许多目前未解决的问题。目标1和2 拟议的研究将确定单个口服微生物组酸应激的反应的范围，分类单元或社区环境。该提案的目标3将阐明如何保护这些UFA。介导的伤害。这些目标将使用生物信息学工具，基本的分子微生物学，与生态相关且复杂的体外口服生物膜模型，以及质谱/脂肪组学。成功的拟议研究的完成将回答有关汽车发病机理的相关问题物种设置，很可能打开调查新型抗野鸡疗法的大门，而这些疗法靶向嗜酸剂，功能不管链球菌的存在和抽象如何。候选人，博士乔纳森·贝克（Jonathon Baker）对牙科汽车的微生物学很长一段兴趣。完成K99后（指导的）该奖项的阶段，他的目标是成为一所领先的研究大学的独立PI，在那里他计划继续研究细菌对膜进行对抗的修饰环境压力，同时利用获得的数据来开发新的治疗。资助的K99/R00 提案将使贝克博士能够发展所需的技能，以完成拟议的研究（培训质谱/脂肪组学），随后成为一名独立的研究科学家（教学培训贝克博士的导师，维克多·尼兹特（Victor Niizet）和彼得·多雷斯坦（Pieter Dorrestein），以及环境（J. Craig Venter Institute和UC San Diego）已仔细选择，以提供高质量的，潜水员的科学和大学支持以及最先进的设施，以确保成功完成该研究计划和拟议的职业发展目标。