This is an MCSDA application that proposes a 5-year educational program for Dr. Salvador Nares at the Baylor College of Dentistry. The program will combine a PhD study in biomedical sciences and training leading to a specialty certification in periodontics. A research proposal is provided which combines Dr. Nares' interest in clinical periodontics and cellular and molecular mechanisms of phenytoin (PHT) induced gingival overgrowth. Approximately 2 million people take phenytoin to prevent seizures and approximately 1/2 of these have been described as developing gingival overgrowth. While this phenomenon has been identified and known for many years the molecular events and the selectivity of individuals who develop this is still not known. The investigator proposes to address the clinical problem of phenytoin induced gingival overgrowth using a basic science approach which examines cellular molecular mechanisms by which PHT can alter monocyte and macrophage phenotypes. Minimal information is available regarding the ability of PHT to alter monocytes and macrophages at the cellular molecular level and the author proposes three general concepts related to this. First, PHT has a direct or indirect effect on gene expression for surface antigens or growth factor at a transcriptional, post-transcriptional or translational level in th macrophages. Second, PHT alters intracellular signaling pathways and these are reflected in intracellular calcium concentrations, inositol phosphate turnover or changes in transmembrane potential. And, finally the potential that PHT provides a signal that converts monocytes into a fibroblast-like cell capable of proliferation and overproduction of collagen in the local environment leading to the overgrowth and fibrosis. The author proposes to use cultured human peripheral blood monocytes as a model system. The outcome proposed is that a better understanding of how PHT modulates monocyte and macrophage biology may lead to development of new therapeutic strategies for diseases characterized by connective tissue overgrowth.
