Regeneration of the periodontium is one of the ultimate goals of periodontal therapy. To achieve successful regeneration, we must have a thorough understanding of the cellular and molecular biologic events in the given tissue. The extracellular matrix glycoproteins - tenascin (Tn) and fibronectin (Fn) are prominently expressed during embryonic development and wound healing. The proposed studies are aimed at analyzing the biologic functions of specific domains of Tn and Fn using in vitro and in vivo assays. In the first specific aim of the continuing proposal, we will continue studies on the mapping of functional domains of Tn. All the members of the Tn family (Tn-C and its two paralogues Tn-R and Tn-X) have the last three Fn-III repeats and the C-terminal fibrinogen-like domain well conserved. Since this region in Tn-C has cell- and heparin-binding activity, we will further characterize the biologic activity in this region. We will test the hypothesis that the C-terminal ends of TnC, TnR and TnX have significant biological activities. These would include mediating cell-cell adhesion (important in events such as angiogenesis and epithelial cell migration in healing wounds), downregulating cell proliferation, and probably affecting programmed cell death. In the second specific aim, the biologic functions of the alternatively- spliced domains EIIIB and ElIIA of human Fn will be characterized in detail. Preliminary data shows that the presence of these domains enhances cell adhesion at low concentrations. We will test the hypothesis that domains EIIIB and for EIIIA of human Fn serve important functions during development and wound healing by either conformational modifications or having their own novel sites with biologic activities. The structural and biologic effects of including these domains in recombinant human Fn fragments will be studied. In the third specific aim, we will examine periodontal wound healing/tissue regeneration and bone matrix-induced endochondral bone formation in TnC-/- (TnC knockout mice) mice. Since TnC is prominently expressed during cartilage/bone formation and in the adult periodontal ligament, we expect to see differences in the healing events in TnC-1- mice compared to the TNC +/- and TNC +/+ mice. The date from these studies should shed some important light on the biologic functions of Tn and Fn. Information gained from these studies will be used to develop strategies for biochemically-mediated healing and regeneration of periodontal tissues where recombinant polypeptides of these proteins can be used to enhance specific cellular events.
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