This application proposes to study in depth the role of inflammatory and angiogenic receptor signaling processes within the vasculature and combines five interactive projects with the support of four cores to achieve an understanding of signaling pathways mediated by polypeptide growth factors and cytokines in mesoderm-derived cells. These projects include collaborative research efforts between eight investigators interested in the cell and molecular biology of vessel wall function and these include, (1) the mechanism of the fibroblast growth factor-1 secretion pathway, (2) the catabolism of lipoproteins, protease and protease-inhibitor complexes by the very low density lipoprotein receptor and its receptor-associated protein antagonist, (3) the regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatases, (4) mechanisms of prostanoid-mediated vascular pathology utilizing transgenic expression of the cyclooxygenase-1 gene, and (5) the functional characterization of a novel protein kinase encoded by a mitogen-inducible gene. These interactive research efforts will be supported by an administrative core to provide logistics and operational support and a protein and nucleic acid chemistry core, an experimental pathology core and an immunology core to provide expertise in these areas. This application evolved from the efforts of a very productive NHLBI SCOR in Transfusion Medicine from which numerous interactive collaborations were created. It is anticipated that the contributions derived from research and support efforts will generate new insight into the molecular mechanisms responsible for the regulation of vascular pathology.
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