The central theme addresses the structural issues of function of the cellular initiation and subsequent thrombogenic, inflammatory, and pathogenetic pathways and impact of the initiating cellular receptor and cofactor, namely Tissue Factor (TF). We will advance knowledge of the localization and requirements for TF to assemble the various complexes that initiate the coagulation protease cascade, how this is controlled at the endothelial and leukocyte surface. We will utilize intravital microscopy as well as genetically modified mice and rodent disease models to advance factual data as to the endothelial aspects of initiation of the thrombogenic and resultant linked cell signaling and inflammatory cascades. We have initial discoveries of novel selective inhibitors of TF initiation of the extrinsic limb of the coagulation protease cascade. This and the fundamental basis of understanding of the in vivo functional aspects of TF expression and its hemostatic and thrombogenic impact are being advanced by computational structural solutions, such as the novel peptidyl inhibitor and search for more advanced compounds. These leads will be explored for potential therapeutic advances in safely attenuating thrombotic disease. The signaling events associated with TF initiation of the cascades is an important central issue that is only very recently emerging. The cell signaling events and their impact on the inflammatory cascades and in disease pathways of ischemia, sepsis, and infarction are integrated in the projects. Again, the use of NMR, crystallography, and computational means of solving the assembly of the TF directed complexes and downstream targets are tools which are highly developed here. Utilizing genetically modified mice, including ones we have developed that now express the inserted human TF gene and protein rather than murine TF, we will advance understanding of TF driven disease processed in vivo and be able to assess the human protein target with interventional molecules such as the current anti-human TF monoclonal antibody for efficacy in reducing the ischemic impact of cardiac arterial occlusion model. These studies have, and will continue to produce original data and advanced knowledge of the TF driven thrombotic and inflammatory diseases and new routes to reduce the impact of these diseases.
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