Diversity supplement for R01DE029479-01A1 to support Dr. Jeremy Elias

R01DE029479-01A1 的多样性补充品以支持 Jeremy Elias 博士

• 批准号: 10648830
• 负责人: Xuesong He
• 金额: $ 14.85万
• 依托单位: ADA FORSYTH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10648830
• 关键词: Acids; Advanced Development; Animal Model; Antimicrobial Effect; Bacteria; Biomass; Buffers; Carbohydrates; Carbon; Caries prevention; Chemical Structure; Chemistry; Chlorhexidine; Chronic; Clinical; Collaborations; Communicable Diseases; Consequentialism; Dental Clinics; Dental Enamel; Dental caries; Development; Dietary Carbohydrates; Effectiveness; Encapsulated; Equilibrium; Feedback; Future; Goals; Growth; Human; In Vitro; Infection prevention; Intake; Kinetics; Knowledge; Length; Microbial Biofilms; Modeling; Monitor; Mus; Names; Oral; Particle Size; Physiological; Production; Property; Research; Saliva; Salts; Series; Silicon Dioxide; Sodium Chloride; Solubility; Stimulus; Streptococcus mutans; Sucrose; Surface; Tail; Testing; Tooth structure; Translating; Water; acronyms; analog; antimicrobial; antimicrobial drug; aqueous; bactericide; base; biomaterial compatibility; cariogenic bacteria; cost; demineralization; design; dysbiosis; effectiveness evaluation; empowered; environmental change; improved; in vivo; innovation; lead candidate; microbial; microbial community; microbial composition; microbiome; multidisciplinary; nanoparticle; novel; oral microbial community; polymicrobial biofilm; polymicrobial disease; prevent; research clinical testing; response; targeted treatment; water solubility

Abstract: In today's microbiome era, it is well-recognized that dental caries, one of the most prevalent and costly chronic infectious diseases world-wide, results from dysbiosis of the oral microbiota and the oral environmental changes that cause tooth damage. Specifically, frequent intake of fermentable carbohydrates promotes a progressive shift in microbial composition toward acidogenic and acid-tolerant species. The continual acid- induced demineralization eventually overcomes the buffering capacity and anti-microbial properties of saliva, leading to irreversible tooth destruction. The goal of this proposed research is to prevent dental caries through targeted treatment of acid-producing bacteria (t-TAB). t-TAB will facilitate a healthy microbial community that are vital in modulating pH and preventing acid-induced teeth damage. The t-TAB will be achieved by selectively inhibiting the growth of cariogenic bacteria through enhanced antimicrobial (AM) efficacy in response to the accelerated/aggravated caries-causing acid production in comparison to commensal species. We propose four specific aims to develop, identify and assess the effective t-TAB candidates. In Specific Aim 1, we will synthesize and characterize six new pH-sensitive quaternary pyridinium salts (pH-QPSs). We expect to identify compounds or combinations of compounds that provide t-TAB in aqueous mixtures. We will enhance our understanding of the chemical structure/AM efficacy relationship and optimize the AM efficacy and solubility of pH-QPS(s) to obtain safe and effective t-TAB treatment. In Specific Aim 2, we will empower a clinically tested AM agent, chlorhexidine (CHX), with pH-sensitive AM efficacy (pH-AM-E) and transform it into a t-TAB agent. We will achieve acid enhanced CHX release through encapsulated CHX in QPS-functionalized mesoporous silica nanoparticles. We will also identify the synergistic pH-AM-E induced by interactions of CHX and pH-QPSs. In Specific Aim 3, we will assess and compare the t-TAB efficacy of lead candidates from Aim 1 and Aim 2 by employing a multispecies biofilm model that simulates human oral microbial community (named O-mix). The t- TAB efficacy will be assessed in the presence and absence of sucrose—the cariogenic dietary carbohydrate. Strategy will entail evaluating biomass, analyzing microbial profiles and determining environmental pH. Finally, the most effective t-TAB candidates that successfully inhibit the growth of cariogenic acid-producing bacteria while keeping the commensal species in working conditions, e.g., maintaining pH above 5.5, will be further assessed in Specific Aim 4 in vitro using an in vitro microbial-caries model on human enamel and in vivo employing a well-developed mouse caries model. Successful completion of the proposed aims will provide new materials for oral rinse in dental clinics to prevent/treat dental caries. Knowledge gained from this study will also advance material development to prevent infection and erosion.

摘要：在当今的微生物组时代，人们认识到龋齿是最普遍，最昂贵的牙齿之一 全世界的慢性传染病，口腔菌群的营养不良和口腔环境引起的 改变牙齿损坏的变化。具体而言，经常摄入可发酵的碳水化合物会促进 微生物组成向酸性和耐酸物种进行了逐步转移。连续酸 - 诱导的脱矿化最终克服了唾液的缓冲能力和抗微生物特性， 导致不可逆转的牙齿破坏。这项拟议研究的目的是防止龋齿通过 靶向产生酸性细菌（T-TAB）的靶向治疗。 T-TAB将促进一个健康的微生物社区 对于调节pH值和防止酸引起的牙齿损伤至关重要。 t-tab将通过选择性实现 通过增强的抗菌（AM）效率来抑制致肉源性细菌的生长 与共生物种相比，加速/加重引起龋齿的酸产生。我们提出了四个 开发，识别和评估有效的T-TAB候选者的具体目的。在特定目标1中，我们将合成 并表征了六个新的pH敏感的四吡啶盐盐（pH-QPSS）。我们希望识别化合物 或在水性混合物中提供T-tab的化合物组合。我们将增强我们对 化学结构/AM效率关系，并优化pH-QPS的AM效率和溶解度 获得安全有效的T-TAB处理。在特定的目标2中，我们将授权经过临床测试的AM代理， 用pH敏感的AM效率（pH-AM-E）的氯己定（CHX）转化为T-tab剂。我们将 通过在QPS官能化的介孔二氧化硅中封装的CHX实现酸增强的CHX释放 纳米颗粒。我们还将确定由CHX和pH-QPS相互作用引起的协同pH-AM-E。在 特定目标3，我们将评估和比较AIM 1的铅候选者的T-tab效率，并通过 采用模拟人类口腔微生物群落的多物种生物膜模型（命名为O-Mix）。 T- 在存在和不存在蔗糖的情况下，将评估TAB效率 - 商饮食中的碳含碳水化合物。 策略将需要评估生物质，分析微生物谱并确定环境pH值。最后， 最有效的T-TAB候选者成功抑制了产生酸性细菌的生长 在将共生物种保持在工作条件下的同时，例如将pH值保持在5.5以上，将进一步 在特定目标4中使用体外微生物 - 帕里斯模型在体外评估人牙釉质和体内 采用发达的小鼠携带模型。成功完成拟议的目标将提供新的 口腔冲洗的材料在牙科诊所预防/治疗龋齿。从这项研究中获得的知识也将 提高材料开发以防止感染和侵蚀。