Modulation of MMPs gene expression and activity by the microbiome in caries

龋齿中微生物组对 MMP 基因表达和活性的调节

• 批准号: 10440511
• 负责人: Cristina De Mattos Pimenta Vidal
• 金额: $ 14.5万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10440511
• 关键词: Address; Adult; Age; Award; Bacteria; Biochemical; Bioinformatics; Biology; Cells; Clinical; Communication; Complex; Data; Dental; Dental Enamel; Dental Pulp; Dental caries; Dentin; Dentin Formation; Dentistry; Development; Diet; Disease; Disease Progression; Due Process; Ensure; Environment; Enzyme Activation; Enzymes; Esthetics; Etiology; Excision; Extracellular Matrix; Filtration; Foundations; Future; Gene Expression; Genetic; Genomics; Goals; Health; Immune response; In Vitro; Infiltration; Interdisciplinary Study; Knowledge; Lead; Leadership; Left; Lesion; Maps; Mediating; Mentors; Mentorship; Metalloproteases; Methodological Studies; Microbiology; Minerals; Modeling; National Health and Nutrition Examination Survey; Odontoblasts; Operative Surgical Procedures; Oral; Pathology; Pattern recognition receptor; Peptide Hydrolases; Population; Process; Property; Proteinase-Activated Receptors; Proteins; Proteomics; Publications; Research; Research Personnel; Research Support; Research Training; Resources; Role; Salivary; Scientist; Structure; Testing; Time; Tissues; Tooth Loss; Tooth structure; Training; Undifferentiated; United States; Writing; base; career; career development; cariogenic bacteria; collagenase; cost; demineralization; design; dietary; effective therapy; experience; experimental study; host microbiome; in vivo; innovation; insight; member; microbial composition; microbiome; microorganism; mineralization; new therapeutic target; novel; novel therapeutics; oral microbiome; permanent tooth; prevent; protein expression; remineralization; repaired; reparative process; restoration; screening; skills; sound; stem cells; tissue repair; young adult

Project Summary/Abstract Caries is a multifactorial disease that results from an imbalance between the microbiome and the host leading to demineralization of the dental hard tissues. After a lesion initiates in enamel, further tissue demineralization will lead to cavitation and involvement of the dentin. The etiology of caries attributes lesion progression to diet- and pH-dependent processes. However, enamel and dentin differ in terms of mineral content, structure and composition, and the degradation of the organic matrix of dentin seems to be a more complex mechanism than currently accepted. In vitro studies from the candidate’s research group and from others have shown in- creased presence and activity of endogenous proteases, such as matrix metalloproteases (MMPs), in caries dentin. Novel and important preliminary data suggest that while some MMPs may contribute for tissue degra- dation, specific MMPs might be important to favor reparative processes in dentin, even though tissue repair does not overcome degradation in advanced caries lesions. Fundamental questions remain concerning the regulatory mechanisms that drive MMPs expression and activation and how these mechanisms respond to bacterial infiltration as caries lesion advances. This proposal will address these issues by: (a) filling the gap in knowledge regarding the breadth of the contribution of specific MMPs to caries lesion progression; (b) defining the role of odontoblast-produced and dentin-released MMPs in caries; and (c) determining how the shift in the oral microbiome can modulate MMPs expression and/or activation as the lesion progresses. These studies will provide essential baseline information to facilitate the candidate’s long-term research goal, which is the devel- opment of new dental therapies based on modulation of MMPs activity in caries. The candidate aims to be- come an independent researcher to pursue the creation of novel therapeutic targets based on selective inhibi- tion of damaging endogenous mechanisms and promotion of repair mechanisms that would fundamentally change the way in which we manage and surgically treat dentin caries. This application for a K08 award will provide the candidate protected time and training to support her research goals and to ensure her career de- velopment. The candidate has assembled an outstanding group of mentor, co-mentors, collaborators, consult- ant, and advisors with expertise in microbiology, genomics, proteomics, and bioinformatics. This K08 award will facilitate the candidate’s career development by providing the structure and the guidance for expanding and acquiring: (1) advanced knowledge on dentin organic matrix composition and biochemical properties in health and caries disease, (2) experience with methodologies for the study of oral proteins and microorganisms in caries, including genomics and proteomics, (3) skills in leadership and scientific communication including writing, oral presentations and mentorship, and (4) the protected time and the resources to generate data and publications to support an R01 application by the end of the award period.

项目摘要/摘要 龋齿是一种多因素疾病 牙齿硬组织的浸润。在搪瓷中引发病变后，进一步的组织充 将导致牙本质的气蚀和参与。龋齿的病因属性病变的进展为饮食 - 和pH依赖性过程。但是，搪瓷和牙本质在矿物质含量，结构和 组成，牙本质有机基质的降解似乎比 目前接受。候选人研究小组和其他研究的体外研究表明 龋齿中内源性蛋白酶的存在和活性，例如基质金属蛋白酶（MMP） 牙本质。新颖而重要的初步数据表明，尽管某些MMP可能有助于组织脱脂 染色，特定的MMP可能对牙本质中的修复过程可能很重要，即使组织修复 不会克服晚期龋齿病变中的降解。基本问题仍然关注 驱动MMP表达和激活的调节机制以及这些机制如何响应 随着龋齿病变的进展，细菌浸润。该建议将通过：（a）填补差距 关于特定MMP对病变进展的贡献的知识； （b）定义 Odontoblast产生的和牙本质释放的MMP在携带中的作用； （c）确定如何转移 口服微生物组可以随着病变的进展调节MMP的表达和/或激活。这些研究会 提供必要的基线信息，以促进候选人的长期研究目标，这是开发的 基于龋齿中MMP活性的调节的新牙科疗法的选择。候选人的目标是 成为一名独立研究人员，以选择性抑制作用创建新的治疗靶标 损害性内源性机制和促进修复机制的促进 更改我们管理和手术治疗牙本质汽车的方式。此申请K08奖将 提供受保护的时间和培训，以支持她的研究目标并确保自己的职业生涯 速度。候选人组建了一群杰出的导师，联合委托人，合作者，咨询 - 蚂蚁和具有微生物学，基因组学，蛋白质组学和生物信息学专业知识的顾问。这个K08奖 通过提供扩展的结构和指导来促进候选人的职业发展 和获取：（1）关于牙本质有机基质组成和生化特性的高级知识 健康和龋齿疾病，（2）研究口服蛋白质和微生物的方法的经验 在包括基因组学和蛋白质组学在内的龋齿中，（3）领导和科学交流的技能 写作，口头演示和指导职位，以及（4）受保护的时间以及生成数据和的资源 在奖励期结束之前支持R01申请的出版物。