We seek support for continued development and operation of an interdisciplinary Research Center in Oral Biology. The purpose of the Center is to assist in the national effort to reduce the toll of oral disease, and to promote the general level of oral health. The Center seeks to create a research environment of excellence, to attract investigators of high quality into dental research, to provide challenging opportunities for research training, and to foster research-related relationships with other institutions. Our goal is to contribute in a significant way to the foundation of basic knowledge necessary for studies aimed at resolution of important clinical conditions. Our efforts focus on elucidation of mechanisms of signaling between and among cells, and between cells and the components of extracellular matrix (ECM), including signaling molecules such as cytokines and growth factors. Our concepts and technologies are drawn from the forefront of modern molecular and cell biology. We will determine mechanisms by which cell-to-cell signals among B lymphocytes, T lymphocytes, and follicular dendritic cells are coordinated and regulated during activation and maturation of human B lymphocytes into antibody- producing cells. The components of the ECM are now known to exert major effects on cell responses to regulatory molecules such as the cytokines. We have discovered that three genes, rather than one, exist for thrombospondin (TSP), an extracellular protein that participates in modulation of cell-ECM interactions. We will clone and express these three genes, analyze their regulation, and determine the biologic function of the TSPs. Similarly, we have established that the complement protein C1q is a participant in fibroblast-ECM interactions, and that fibroblasts express a receptor for C1q. We will isolate and characterize the C1q receptor expressed by fibroblasts, generate antibodies, and elucidate mechanisms by which C1q modulates such opposing functions as adhesion and detachment. A unique mitogenic protein has been detected and isolated from human tooth root cementum. We will clone the gene for this mitogen, express it in vitro, and explore the biology of the mitogen. We will determine which cells of the periodontium make it and which respond to it, and we will identify its receptor. Mitogen-binding activates complex intracellular pathways culminating in DNA synthesis and cell replication. Polyamines play a key role. The enzyme ornithine decarboxylase (ODC) is the key regulated enzyme in polyamine synthesis. The promoter portion of the gene for this enzyme is complex and serves as a model for analysis of promoter activity. We will elucidate the pathways by which protein kinases A and C participate in promoter regulation, and identify the region of the promoter through which the cytokine IL-1 upregulates gene activation. Completion of our studies will provide a strong basic science foundation for resolution of clinical problems, including regeneration of periodontal connective tissue.
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