PROPOSAL SUMMARY There is an increasing need to develop novel strategies within vital pulp treatment (VPT) to address limitations in existing therapies and to help overcome tooth injury due to caries, restorative procedures or trauma. Currently, there remain significant gaps in our knowledge regarding the molecular and cellular mechanisms that regulate tertiary dentinogenesis and wound healing of pulp tissues after injury. This knowledge plays a critical role in preserving pulp tissues after damage caused by caries and traumatic injury. Our long-term goal is to design new biologically-based strategies aimed at modulating pulpal inflammation in cases of advanced pulpitis, as well as to create novel regenerative techniques to therapeutically target biological processes to stimulate repair of dental pulp. The objective for this application is to elucidate how MMP13 specifically regulates the dental pulp’s reparative processes as well as the immunological response in acute pulpitis. The overarching hypothesis is that MMP13 stimulates tertiary dentin formation and regulates progression of the pulpal inflammatory response in the damaged dentin- pulp complex. Guided by strong published and preliminary data, this hypothesis will be tested by pursuing the following three specific aims: Aim 1: Determine the influence of MMP13 on reactionary and reparative tertiary dentin formation, Aim 2: To determine the molecular and cellular mechanism by which MMP13 regulates the immunological response in pulpitis, and Aim 3: Translate MMP13’s role in tertiary dentin formation and pulpitis to human tissues. Conditional (odontoblast or myeloid cells specific) MMP13 knockout mice will be used to achieve the first two aims and the third aim will employ ex vivo human tissue models. Importantly, initial characterization of our models indicates that MMP13 involved in tertiary dentin formation as well as inflammatory response after tooth injury in vivo. Translationally, our data will lead to the identification and understanding of important mediators, so that novel targeted therapeutic solutions can be designed within Cariology and Regenerative Endodontics. This will lessen the burden of existing therapies aimed to treat damaged pulp affected by caries and traumatic injury.