Project Summary Tooth loss from trauma or disease remains a significant world-wide concern due to poor esthetics and loss of function. Addressing this issue is not trivial because regeneration of alveolar bone and oral tissue is not predictable, partially due to the complexity of the process. Bone regeneration of these defects remains unpredictable and understanding the physiological mechanisms that guide bone marrow biology and inflammatory resolution will increase the therapeutic reliability of these regenerative techniques in the future. We have observed a previously unknown role for Growth Arrest Specific 6 (GAS6) in controlling alveolar bone and soft tissue regeneration following extraction. GAS6-deficient mice showed markedly worse healing following extraction, which was associated with aberrant bone and immune phenotypes. The primary goal for this K99/R00 proposal is to test the critical role of GAS6 in oral tissue healing. Two specific aims are proposed based on our previous observations. We hypothesize that GAS6 acts directly on mesenchymal stem cells to prime them towards a osteoblastic phenotype. This hypothesis will be tested through measurement of healing following extraction in mice with mesenchymal stem cells deficient in GAS6 signaling, along with associated experiments on primary cells derived from patients following extraction. We also hypothesize that increased neutrophil infiltrate in GAS6-deificiency impedes soft tissue healing. We will employ conditional knockout models of neutrophils and neutrophil functions to test this hypothesis. The K99 portion will be dedicated to developing new tools for studying tissue and immune cell-specific GAS6 signaling and building upon my prior work in osteoblast biology, while the R00 portion will deploy these tools to study inflammation and connect alveolar regeneration with GAS6 signaling. This award will provide a significant contribution to the understanding of the physiology of healing in the oral cavity while providing significant training to the candidate in the use of genetic mouse models and immunology, ultimately leading to an independent career as a dental clinician-scientist specializing in treatment of systemically compromised patients.