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

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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.