Making a quantum leap in plaque research with modern sciences

利用现代科学实现牙菌斑研究的巨大飞跃

• 批准号: 8064383
• 负责人: Renate Lux
• 金额: $ 37.43万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8064383
• 关键词: 10 year old; Acids; Address; Adult; Bacteria; Behavior; Biological; Biological Process; Biology; Carbohydrates; Caries prevention; Characteristics; Chemistry; Child; Clinical Management; Collaborations; Communities; Complex; DNA; Data; Dental; Dental Enamel; Dental Plaque; Dental caries; Dentistry; Detection; Development; Dietary Carbohydrates; Dimensions; Disease; Disease Progression; Dyes; Ecology; Effectiveness; Engineering; Environment; Epidemic; Excision; Fermentation; Fluorescent Dyes; Fluorescent Probes; Fluorides; Future; Gingiva; Goals; Green Fluorescent Proteins; Health; In Situ; Incidence; Incubated; Individual; Institutes; Isotopes; Knowledge; Label; Laboratories; Laser Scanning Confocal Microscopy; Lead; Learning; Left; Link; Malnutrition; Maps; Measures; Mechanics; Mediating; Metabolic; Metabolism; Methods; Microbial Biofilms; Mission; Molecular Biology; Monitor; Monoclonal Antibodies; National Institute of Dental and Craniofacial Research; Oral; Oral Microbiology; Oral cavity; Oral health; Organism; Pacific Northwest; Pathogenesis; Peptides; Population; Prevalence; Process; Production; Property; Proteins; Public Health; RNA; Research; Research Personnel; Role; Saliva; Sampling; Schools; Science; Source; Spatial Distribution; Stimulus; Streptococcus mutans; Sucrose; System; Techniques; Technology; Testing; Therapeutic Effect; Time; Treatment Cost; Treatment Protocols; United States; Virulence; Work; antimicrobial; antimicrobial peptide; base; cariogenic bacteria; commensal microbes; improved; in vivo; insight; interest; killings; microbial; microbial community; microbicide; microorganism; new therapeutic target; novel; novel strategies; novel therapeutic intervention; oral bacteria; oral biofilm; oral pathogen; oral plaque; organic acid; pathogen; prototype; public health relevance; quantum; research study; stable isotope; success; tool

DESCRIPTION (provided by applicant): Current tooth decay (dental caries) prevention methods include enamel hardening with fluoride and bacterial removal via mechanical and general antimicrobial approaches. These methods are based on the knowledge that oral plaque bacteria ferment dietary carbohydrates to produce pH-reducing organic acids. Initial reductions in caries incidence observed upon widespread implementation of these measures reached a plateaudecades ago. Today more that 40% of children under 10 years of age as well as more than 85% of the adult population in the United States still suffer from the disease that cause annual treatment cost of $ 80 billion. Further development of these "remove and kill all" approaches are not likely to significantly improve oral health. Revolutionary advancements can only be achieved by expanding our understanding of the microorganism- mediated processes leading to tooth decay. This will require a detailed picture of dental plaque organisms, their metabolic activities and interactions. The long-term objective of this application is to combine and apply (established) advanced technologies to provide a detailed understanding of the biological processes involved in cariogenesis. This will include a comprehensive analysis of the cariogenic potential of known pathogens and their influence on acid production. Furthermore, we will provide information on the metabolic activity of species whose function in acid production is currently unknown. In compliance with the mission of the NIDCR we will further develop targeted strategies against the current caries epidemic based on current knowledge and the new information developed with the advanced technologies in this project. We will combine sophisticated, species-specific in vivo labeling tools (monoclonal antibodies and fluorescent protein-expressing bacteria) with monitoring of acid production (pH-sensitive dyes, fluorescent proteins and NMR profiling), labeling of acid active species with stable isotope probing (SIP). These tools will reveal details of the processes in dental plaques regarding species, interspecies interactions and the metabolic processes contributing to cariogenic (acid-producing) or healthy (homeostatic) conditions. The second goal of this application will examine the potential of our previously developed specifically targeted antimicrobial peptides (STAMPs) against cariogenic Streptococcus mutans to shift plaque ecology towards a healthy plaque. We will further improve a current prototype antimicrobial peptide that is activated in acidic environments and develop more antimicrobial peptides against known cariogenic species as well as those identified in this project. This study will greatly expand our knowledge of the biological processes within plaques that lead to disease and provide novel therapeutic approaches that aim to achieve long-term oral health by specifically removing cariogenic species and leaving beneficial or harmless populations intact. PUBLIC HEALTH RELEVANCE: Relevance to public health statement Tooth decay (caries) remains a major health issue in the United States and worldwide with a prevalence of more than 50% in young children that increases to about 85% in the adult population. The consequences of this disease range from a significant number missed days at school or work to malnutrition and effects on overall health, and result in about $80B in treatment costs. Caries disease-progression studies and resulting treatment regimen have not yielded significant oral-health improvements in several years. We propose to revisit the processes involved in caries development by combining carefully chosen and highly complementary new analytical and molecular biology tools. These tools will identify the roles of individual species and their characteristics involved in the acid production that leads to tooth decay. This new approach will provide a deeper understanding of tooth-decay progression and allow for the subsequent development of novel targeted therapeutic approaches to eliminate "bad" bacteria from the mouth for a long-term change to better oral health.

描述（由申请人提供）：目前的蛀牙（龋齿）预防方法包括用氟化物硬化牙釉质和通过机械和一般抗菌方法去除细菌。这些方法基于口腔菌斑细菌发酵膳食碳水化合物以产生pH降低有机酸的知识。在广泛实施这些措施后观察到的龋齿发病率的初步下降在几十年前达到了一个平台。今天，美国超过40%的10岁以下儿童以及超过85%的成年人口仍然患有这种疾病，每年的治疗费用为800亿美元。进一步发展这些“清除和杀死所有”的方法不太可能显著改善口腔健康。革命性的进步只能通过扩大我们对微生物介导的导致蛀牙的过程的理解来实现。这将需要详细了解牙菌斑微生物、它们的代谢活动和相互作用。本申请的长期目标是联合收割机并应用（已建立的）先进技术，以提供对龋齿发生中涉及的生物过程的详细了解。这将包括对已知病原体的致龋潜力及其对产酸的影响的全面分析。此外，我们还将提供有关其在产酸中的功能目前尚不清楚的物种的代谢活性的信息。根据NIDCR的使命，我们将根据现有知识和本项目中先进技术开发的新信息，进一步制定针对当前龋齿流行的有针对性的战略。我们将结合联合收割机复杂的，物种特异性的体内标记工具（单克隆抗体和荧光蛋白表达细菌）与监测酸生产（pH敏感染料，荧光蛋白和NMR分析），标记酸活性物种与稳定同位素探测（SIP）。这些工具将揭示牙菌斑中有关物种、物种间相互作用和导致致龋（产酸）或健康（稳态）条件的代谢过程的细节。本申请的第二个目标将检查我们先前开发的针对致龋变形链球菌的特异性靶向抗菌肽（STAMP）将菌斑生态转向健康菌斑的潜力。我们将进一步改进目前的原型抗菌肽，在酸性环境中被激活，并开发更多的抗菌肽对已知的致龋物种，以及在这个项目中确定的。这项研究将极大地扩展我们对斑块内导致疾病的生物学过程的了解，并提供新的治疗方法，旨在通过特异性去除致龋物种并保持有益或无害人群的完整性来实现长期口腔健康。 公共卫生关系： 与公共卫生声明的相关性蛀牙（龋齿）仍然是美国和世界范围内的主要健康问题，在幼儿中的患病率超过50%，在成年人群中增加到约85%。这种疾病的后果从大量缺课或工作到营养不良和对整体健康的影响，并导致约800亿美元的治疗费用。龋齿疾病进展研究和由此产生的治疗方案在几年内没有产生显着的口腔健康改善。我们建议通过结合精心选择和高度互补的新的分析和分子生物学工具，重新审视龋病发展所涉及的过程。这些工具将确定个别物种的作用及其在导致蛀牙的酸产生中的特征。这种新方法将提供对蛀牙进展的更深入了解，并允许随后开发新的靶向治疗方法，以消除口腔中的“坏”细菌，从而长期改善口腔健康。