This Program Project Grant, entitled """"""""THROMBUS FORMATION IN VIVO"""""""" brings four principal investigators to focus on the process of thrombogenesis. This group has pioneered the development of high speed intravital confocal and widefield microscopy to study thrombus formation in a living mouse using the laser induced thrombosis model. Using this technology, they will address a series of critical questions related to the three phases of thrombus formation: initiation, development and propagation. In Project #1 entitled TISSUE FACTOR AND THE INITIATION OF THROMBUS FORMATION, Dr. Bruce Furie will study the physiologic role of tissue factor and the molecular basis of tissue factor activation. He will examine the kinetics of expression of tissue factor forms in cultured endothelial cells and during thrombus formation in a living mouse. The cellular source of tissue factor required during thrombus formation will be evaluated using chimeric mice, MAFIA mice, and genetically altered mice that are deficient in tissue factor in endothelial cells, platelets, myeloid cells or smooth muscle cells. In Project #2 entitled PLATELET PROTEIN PALMITOYLATION AND THROMBUS FORMATION, Dr. Robert Flaumenhaft will evaluate the role of protein palmitoylation in platelet activation and thrombus formation using the mouse thrombosis model, and determine which proteins undergo posttranslational palmitoylation. In Project #3 entitled CD39 AND ITS ROLE IN THROMBOGENESIS, Dr. Simon Robson will test the hypothesis that modulated CD39/NTPDase-1 expression regulates nucleotide-mediated signaling in the vasculature and platelet activation, thus regulating thrombus propagation during thrombus formation in living mice. In Project #4 entitled INITIAL PLATELET ADHESION AND THROMBUS PROPAGATION, Dr. Barbara Furie will study the combined roles of GPVI/PAR4 and PAR4/von Willebrand factor in platelet activation during thrombus formation, the contribution of cellular sources of von Willebrand factor to thrombus development and the role of Factor XII and Factor IX in tissue factor-mediated thrombus propagation. Administrative, Intravital Microscopy and Mass Spectrometry cores support the activities of the four projects. The ability to study the biochemistry and cell biology of thrombus formation in living animals offers opportunities to understand thrombosis and develop strategies for preventing thrombosis, the major cause of morbidity and mortality in Western society.
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