The purpose of core A is to provide investigators in the Program Project with access to standardized procedures for the study and quantitative description of processes relevant to thrombus formation under the influence of defined flow forces, in ex vivo models or within the circulatory system of a whole animal. Moreover, the core will help investigators with the isolation and/or culture of relevant vascular cells under static and flow conditions. Project 1 (Ruggeri) will utilize ex vivo perfusion chambers to study the volume of thrombi deposited on selected thrombogenic substrates, including different types of purified collagens and different extracellular matrices (ECMs) under conditions mimicking different hemodynamic environments. Project 1will utilize intravital microscopy techniques to study thrombus formation in different mice with targeted alterations of platelet and matrix proteins. Project 1 will use 40% of core A resources. Project 2 (Ginsberg) will utilize the core service to isolate endothelial cells from mice with targeted mutations of proteins relevant to fibronectin matrix assembly and will study the effect of shear forces on the structure and thrombogenicity of deposited ECM. Project 2 will also study the effects of inhibitors of specific signaling pathways on the alignment of stress fibers in endothelial cells exposed to shear stress, and the possible related changes in matrix thrombogenicity. Project 2 will use 15% of core A resources. Project 3 (Ruf) will study several aspects of tissue factor (TF) functional modulation using endothelial cells and fibroblasts prepared in core A. Specifically, project 3 will examine the mechanisms through which TF becomes associated with ECM, and whether cryptic TF in matrices becomes active through oxidation. Project 3 will use 15% of core A resources. Project 4 (Griffin) will use intravital videomicroscopy to study the antithrombotic properties of wild type and mutant activated protein C. Project 4 will use 30% of core A resources.
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