The goal of this proposal is to determine the structure, function, and biological relevance of tenascin in the vascular system. This project is based on the applicants a recent success in the identification of the fibrinogen-like domain of Tenascin-C that promotes adhesion and migration of vascular smooth muscle cells. The applicant has mapped the activity to a peptide located near the C-terminal part of this domain. A novel 6 transmembrane protein which may function as a tenascin receptor was cloned. The structure of this protein displayed strong similarity to the plasma membrane calcium channel gene family of proteins. In addition the applicant has demonstrated that tenascin up regulates the metalloproteinase activity of cultured macrophages and smooth muscle cells. Furthermore, the applicant shows that the epidermal growth factor-like domain of tenascin promotes apoptosis of vascular smooth muscle cells. These findings, together with the action of tenascin in other systems, have prompted new questions about the molecular mechanisms responsible for the full range of tenascin actions.
Aim one will define the ability of the new tenascin binding protein to transport calcium and to determine the distribution of the protein in the vascular system.
Aim 2 will determine the effect of the recombinant Fibrinogen-like domain of tenascin on the formation of neo intimal by using a well-validated rat balloon injury model.
Aim 3 will define the potential consequences of the expression of tenascin in human atheroma by determining its effect on the overall metalloproteinase (MMP) activity of intimal cells and apoptosis of vascular smooth muscle cells. Collectively, these studies are likely to expand our understanding of tenascin in smooth muscle cells.
