This program project grant proposal entitled """"""""Structure, Function &Genetics of Coagulation Factors is designed with the overall goal of understanding the initiation and propagation of coagulation in normal and diseased states. Dr. Barrel Stafford, the overall PI and leader of project 1 (Interactions controlling vitamin Kdependent coagulation) will use in vitro and in vivo models to focus on the mechanism of action of FVIIa and FIX as well as studying the reductant for vitamin K epoxide reductase. Dr. Lee Pedersen's project 2 (Structures of complexes of tissue factor &VKD proteins) will use sophisticated molecular modeling techniques to extend known structural data: to construct solvent-equilibrated models that bear on the action of prothrombinase, and to study the regulation of tissue factor, encrypted and unencrypted, bound and unbound to FVIIa. Project 3, directed by Dr. Nigel Mackman (Role of Tissue Factor in Hemostasis &Thrombosis) will focus on the role that tissue factor (TF) plays as the primary cellular initiator of coagulation protease cascades and how its aberrant expression within the vasculature is associated with thrombosis. These studies will involve in part very sophisticated mouse models that allow him to express tissue factor at very low levels and to selectively delete the TF gene in specific cell types. In summary, we present a tightly organized program project proposal that addresses highly significant and novel questions. The success of the overall project is clearly dependent upon the interaction and interdependence of each individual project. The individual projects fit together naturally and the synergism between the projects themselves is enhanced by the synergism that has developed between the investigators involved in the program.
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