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

项目摘要/摘要 龋病是一种多因素疾病，由微生物群和宿主之间的失衡引起。 牙齿硬组织的脱矿。在牙釉质开始病变后，进一步的组织脱矿 会导致空洞和牙本质受累。龋病的病因将病变进展归因于饮食- 和依赖于pH的过程。然而，牙釉质和牙本质在矿物质含量、结构和 牙本质的有机基质的降解似乎是一种比 目前已被接受。候选人的研究小组和其他人的体外研究表明- 龋病中内源性蛋白水解酶的存在和活性增加，如基质金属蛋白酶(MMPs) 牙本质。新的和重要的初步数据表明，虽然一些MMPs可能有助于组织退化- 在牙本质修复过程中，特定的MMPs可能是重要的，即使组织修复 不能克服晚期龋损的降解。根本性的问题仍然是关于 驱动MMPs表达和激活的调节机制以及这些机制如何响应 随着龋损的进展，细菌渗入。该提案将通过以下方式解决这些问题：(A)填补#年的空白 关于特定基质金属蛋白酶对龋损进展的贡献的广度的知识；(B)定义 成牙本质细胞产生的和牙本质释放的基质金属蛋白酶在龋病中的作用；以及(C)确定牙本质中的 随着病变的进展，口腔微生物组可以调节MMPs的表达和/或激活。这些研究将 提供必要的基线信息，以促进候选人的长期研究目标，这是发展- 基于MMPs在龋病中活性调节的牙科新疗法的开发。候选人的目标是- 作为一名独立研究人员，致力于创造基于选择性抑制的新治疗靶点- 破坏内生机制和促进修复机制，这将从根本上 改变我们管理和手术治疗牙本质龋齿的方式。这份K08奖项的申请书将 为应聘者提供受保护的时间和培训，以支持她的研究目标，并确保她的职业生涯 发展。候选人已经组建了一支由导师、合作导师、合作者组成的优秀团队，咨询- Ant，以及在微生物学、基因组学、蛋白质组学和生物信息学方面具有专业知识的顾问。本次K08大奖 将通过提供扩展的结构和指导来促进应聘者的职业发展 获得：(1)牙本质有机基质成分和生化特性方面的高级知识 健康与龋病，(2)口腔蛋白质和微生物研究方法学的经验 在龋齿方面，包括基因组学和蛋白质组学，(3)领导和科学交流的技能，包括 写作、口头演示和指导，以及(4)生成数据和 在授权期结束前支持R01申请的出版物。

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.