Initiation of the coagulation serine protease cascades on cells exposed to blood leads to local thrombin generation and thrombogenesis. Whereas the critical role of thrombin in thrombogenesis is now established, the functional and structural biology of the """"""""initiation complex"""""""" on cells that truly initiates the coagulation cascades to produce thrombin remains at an incomplete descriptive level. The Program Project has been highly focused to elucidate the molecular biology and structural biology of the initiation of thrombosis, the major single cause of morbidity and mortality in this nation. Tissue Factor (TF), a cellular transmembrane receptor and essential cofactor for initiation of coagulation, mediates and regulates the assembly of the initiation macromolecular complex on the surface of cells. Expression of TF and assembly of the """"""""initiation complex"""""""" is the essential initiating event in intravascular thrombin generation. In Sector I we will experimentally address the regulation of transcription of the TF gene in endothelial and relevant cells and its functional expression. In Sector II we will elucidate the structural basis of function of TF to assemble the initiation complex by mutagenesis coupled with discrete functional analyses. We will experimentally establish the molecular basis of assembly of the initiation complex. In Sector III we will solve the three dimensional structure of TF by crystallography and multidimensional NMR. The integration of the data will provide insight and precise knowledge of the initiation of thrombosis and introduce new molecular strategies for molecular intervention. We postulate that this knowledge will provide data and knowledge essential to design of specific, effective and sage therapy of thrombotic and related diseases.
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