This Program Project will advance the central theme of how, why and where the Tissue Factor (TF) dependent thrombogenic case is assembled and controlled and how it influences vascular development, angiogenesis and vascular disease. This will be coupled with exploration of the molecular diversity of the vascular endothelia. We will address and advance knowledge of the precise detail of the structure and structural biology of the TF ternary complex and its assembly with intracellular and extracellular signaling cascades that are important for cellular responses in angiogenesis, vascular development, tumor cell metastasis and invasion, and thrombosis.. Dr. Mackman's Project will address angiogenesis focusing on DNA elements that regulate transient expression of TF by endothelial cells in the process of angiogenesis, the role of transient limited activation of the coagulation protease cascade and resultant cell signaling in angiogenesis, and the role of these in embryonic vascular development. Dr. Rufs' project will address biologic functions of TF beyond those responsible for initiation of intravascular thrombi. The role of the cytoplasmic domain of TF in intracellular signaling will be advanced, exploring the role of actin binding proteins 280, an intracellular ligand for the cytoplasmic tail of TF in cellular migration and successful implantation of metastatic tumor cells. This project will also address the interaction of the TF.VIIa complex with matrix-associated specific inhibitors of the TF pathway and the functional role of accessory intracellular ligands for TF. Dr. Edgington's project will address the cell surface TF ternary complexes Utilizing site specific mutagenesis combined with computational docking the interactive surfaces that mediate formation and function of the initial ternary complex with X substrate will be delineated. The ternary complex retaining the product Xa will be analyzed. The molecular repertoire of the lumenal surface of the endothelium in vivo will be delineated by combinatorial phage display. Dr. Olson's project will develop computational methods for docking of proteins. Computational solutions to the ternary complex and related complexes with substrates IX and Ixalpha, as well as docking solutions for assemblies with the TF-cytoplasmic tail are important to projects 2 and 3.
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