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：
10054501
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：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10054501
关键词：
ATP phosphohydrolase Acids Address Attention Award Bacteria Basic Science Biological Assay Caries prevention Cell membrane Cerulenin Chronic Communicable Diseases Communities Complex Data Data Set Dental Enamel Dental caries Dentistry Diffusion Disease Ensure Environment Enzymes Exhibits Fatty Acids Flow Cytometry Fluorescence Microscopy Fluorides Funding Gene Deletion Genome Goals Health Homologous Gene In Vitro Institutes Investigation Isomerase Lactobacillus casei Lipids Liquid Chromatography Mass Fragmentography Mass Spectrum Analysis Mediating Membrane Membrane Fluidity Membrane Lipids Membrane Proteins Mentors Metabolism Metagenomics Microbial Biofilms Microbiology Modeling Modification Molecular Monitor Oral Oral cavity Organism Pathogenesis Phase Prevalence Prevention strategy Process Production Property Research Research Training Scientist Streptococcus mutans Stress Therapeutic Training Universities Unsaturated Fatty Acids Virulence acid stress anticaries bacterial community bioinformatics tool biological adaptation to stress career development cariogenic bacteria combat community setting demineralization fatty acid biosynthesis fluidity improved inhibitor/antagonist interest lectures medical schools metabolomics metatranscriptomics microbial microbial community mutant novel novel therapeutic intervention novel therapeutics oral bacteria oral biofilm oral microbial community oral microbiome pathogen prevent programs response skills tandem mass spectrometry 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 and environment: Drs. Karen Nelson (J. Craig Venter Institute), Anna Edlund (J. Craig Venter Institute/UC San Diego), Pieter Dorrestein (UC San Diego), Victor Nizet (UC San Diego) and Robert Quivey, Jr. (University of Rochester School of Medicine and Dentistry) 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感染疾病，由酸的形成引起在牙齿表面上产生细菌生物膜，该生物膜脱矿物并破坏保护性的底层搪瓷屏障。有据可查的疾病的当前患病率清楚地表明，仅氟化物并不是因此，在许多情况下预防龋齿。 OFEL预防策略是值得关注的目标。细菌酸是龋齿病原体的必不可少因素。链球菌突变增加了IS质膜中不饱和脂肪酸（UFAS）的前景对环境酸化的反应 - 酸性的适应性。数据表明严重性革兰氏阳性的口服分类单元，包括龋齿相关物种，乳杆菌 Casei，以相似的方式修饰膜，以响应环境酸化。解决了这些观察结果的许多目前未解决的问题。提出的研究确定了这种对整个口服微生物组酸化应激的反应的范围，分类单元或社区环境。介导的损害将使用生物信息学工具，基本分子微生物学，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。支撑研究的压缩将回答相关的问题，认为天主发生物种设置，很可能会为新颖的反卡里治疗剂投资开放靶向嗜酸剂，无论候选链球菌的存在和丰度如何。乔纳森·贝克（Jonathon Baker）对龋齿的微生物学很长一段时间。（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，是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疗法提案将允许博士。质谱/脂肪组学），随后vecome是独立的研究科学家（教学培训贝克博士的导师和环境。 Venter Institute），Anna Edlund（J. Craig Venter Institute/UC San Diego），Pieter Dorreastein（圣地亚哥UC），Victor Nizet（加州大学圣地亚哥加州大学）和小罗伯特·奎维（Robert Quivey）精心选择以提供高贵，多样的科学和大学支持，以及设施，以确保成功地压缩该研究计划和支撑职业发展目标。