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

项目概要/摘要 龋病是一种多因素疾病，由微生物组和宿主之间的不平衡引起， 牙齿硬组织的脱矿作用。在牙釉质损伤后，进一步的组织脱矿 将导致牙本质的空化和受累。龋齿的病因学将病变进展归因于饮食- 和pH依赖性过程。然而，牙釉质和牙本质在矿物质含量、结构和性质方面不同。 牙本质的有机基质的降解似乎是一个比牙本质的有机基质的降解更复杂的机制。 目前接受。来自候选人研究小组和其他人的体外研究表明- 龋齿中内源性蛋白酶如基质金属蛋白酶（MMP）的存在和活性增加 牙本质新的和重要的初步数据表明，虽然一些MMPs可能有助于组织降解， dation，特定的MMPs可能是重要的，有利于修复过程中的牙本质，即使组织修复， 不能克服晚期龋齿病变的降解。基本问题仍然存在， 驱动MMPs表达和激活的调节机制以及这些机制如何响应 随着龋齿病变的进展，细菌浸润。本提案将通过以下方式解决这些问题：（a）填补以下方面的差距： 关于特定MMP对龋齿病变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齿中的作用;以及（c）确定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齿中的变化如何影响成牙本质细胞产生的和牙本质释放的基质金属蛋白酶的作用。 口腔微生物组可以随着病变进展调节MMP的表达和/或活化。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， 基于龋齿中MMPs活性调节的新牙科治疗方法的开发。候选人的目标是- 成为一名独立的研究人员，致力于创造基于选择性免疫的新型治疗靶点， 破坏内源性机制和促进修复机制， 改变我们管理和手术治疗牙本质龋的方式。K 08奖项的申请将 为候选人提供受保护的时间和培训，以支持她的研究目标，并确保她的职业发展， - 谢谢候选人已经聚集了一个优秀的导师，共同导师，合作者，咨询- 蚂蚁，并在微生物学，基因组学，蛋白质组学和生物信息学的专业知识顾问。K 08获奖 将通过提供扩展的结构和指导来促进候选人的职业发展 并获得：（1）牙本质有机基质组成和生物化学性质的先进知识， 健康和龋齿疾病，（2）口腔蛋白质和微生物研究方法的经验 在龋齿，包括基因组学和蛋白质组学，（3）在领导和科学沟通，包括 写作、口头报告和指导，以及（4）受保护的时间和资源来生成数据， 出版物，以支持R 01申请的奖励期结束。

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.