This is a proposal for continuation of a Program Project by a group of established investigators to study basic and clinical aspects of hemostasis and vascular biology with a focus on fibrinogen, fibrin and the vessel wall. The goal of Project 1 will be to define the structural basis of the interaction between fibrin(ogen) and FGF-2 and characterize its functional implications. Specific studies will determine associations and dissociation rate constants for the interaction, identify binding sites involved and determine if other members of the FGF family also bind fibrinogen. Other studies will determine the effect of binding of FGF-2 to fibrin(ogen) on susceptibility to proteolytic degradation and characterize the functional effects of binding including receptor interactions and angiogenesis. The next project will characterize fibrinogen as a component of the extracellular matrix. Specific studies will define the structural domains of fibrinogen and cell surface receptors required for assembly of fibrinogen into matrix, examine cell response, examine structural domains of fibrinogen and cell surface receptors required for assembly of assembly of fibrinogen into matrix, examine cell responses to matrix-associated fibrinogen and determine whether fibrinogen deposition into preformed matrix alters gene expression of matrix cells. Dr. Sporn's project is based on recent observations regarding both pro- and anti-apoptotic signaling mechanisms in endothelial cells infected with R.rickettsii. The pro-apoptotic signaling pathway directly induced by R. rickettsii infection will be characterized to determine if apoptosis involved known signaling transduction pathways involving caspase or generation of reactive oxygen species and dependency and dependency on p53. Other studies will determine if infection protects the cell from other pro-apoptotic stimuli and correlate intracellular infection, induction of apoptosis and NF-kappaB activation in cell culture and ex vivo models. Dr. Fay's project will continue detailed studies of factor VIII interactions in the intrinsic tenase complex. The functional and regulatory interactions between factor VIII and tenase will be characterized in detail. Regulation of tenase by APC will be investigated including the role of endothelial cell binding. Clinical studies will investigate diagnostic and prognostic implications of circulating fibrin(ogen) derivatives, and also evaluate new anti-thrombotic strategies in clinical trials of catheter-directed versus systemic fibrinolysis of deep vein thrombosis, lys-plasminogen as an adjunct for thrombolytic therapy of peripheral arterial occlusion and anti-coagulant strategies for prophylaxis of thrombosis with central venous catheters. The five research projects will be supported by two core facilities devoted to administration and tissue culture. The Program features a focused approach to important problems in hemostasis and vascular biology with a balance between the expertise of fundamental and clinical scientists working collaboratively.
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