Project Summary/Abstract Caries is a multifactorial disease that results from an imbalance between the microbiome and the host, leading to demineralization and destruction of the dental hard tissues. The etiology of caries attributes lesion progres- sion to diet- and pH-dependent processes. However, the specific mechanisms resulting in the degradation of dentin are unclear and have been thought to be mediated exclusively by enzymes from bacteria. New evidence is challenging this concept of advanced caries pathology by suggesting that host-derived enzymes, such as matrix metalloproteases (MMPs) that become activated by changes in the pH, primarily drive the tissue break- down. Recent data indicates that dentin destruction and the response of the dentin-pulp complex to bacteria invasion in caries involve complex enzymatic machinery. Indeed, fundamental questions remain concerning the regulatory mechanisms that drive MMP expression and activation and how these mechanisms are modu- lated by bacterial infiltration as caries lesion advances. The parent award 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. The knowledge generated in the parent award will provide essential baseline information to facilitate the PI’s long- term research goal, which is the development of new dental therapies based on the modulation of MMP activity in caries to stimulate dentin and pulp repair. This new therapeutic approach will be based on selective inhibi- tion of damaging endogenous mechanisms and promotion of repair mechanisms that would fundamentally change the way dentin caries are managed and surgically treated. In addition, a comprehensive career devel- opment plan integrates the research aims with the training activities to allow the PI to achieve the following short-term goals: (1) to acquire advanced knowledge on dentin organic matrix composition and biochemical properties in health and caries disease, (2) enhance experience with methodologies for the study of oral pro- teins and microorganisms in caries, including genomics and proteomics, and (3) develop skills in leadership and scientific communication including writing, oral presentations and mentorship. However, the progress of the parent award was impacted by a critical life event, which delayed the research and career development activities and impacted reaching some of the milestones planned mainly for years 2 and 3 of the parent award. This administrative supplement will support the PI in continuing her career trajectory and returning to full productivity. Achieving the outcomes proposed for the parent award will be essential for the PI to transition to her next career level, sustain a robust res...