This application is for a Program Project Grant from the National Heart, Lung and Blood Institute to support our continuing studies of the mechanism by which blood clotting is initiated. All of our studies to date suggest that the tissue factor pathway is the only significant pathway in a physiological sense. Accordingly, we are proposing a series of definitive experiments relating to the mechanism of action of tissue factor. In Project 1, a kinetic analysis of two tissue factor dependent reactions will be performed. This should shed light on the mechanism of action of this essential cofactor in addition to quantifying the newly described activation of Factor IX. In Project 2, we will be investigating the molecular consequences of the interaction of Factor VIIa and tissue factor. This will be accomplished mainly by active site mapping techniques utilizing competitive inhibitors and by systematically varying substrate composition. In Project 3, we will be investigating the way in which tissue factor is inserted into preformed liposomes, its interaction with Factor VIIa, and developing a radioimmunoassay in a bovine system. This is of particular interest insofar as we have described a plasma inhibitor of tissue factor. In Project 4, we will be attempting to confirm in a human system what we have learned from the bovine. In addition, we will directly compare the efficiency of glass activation of blood coagulation with that induced by tissue factor. In Project 5, which will be performed in a consortium arrangement with Yale University School of Medicine, we will continue our studies on the purification of human tissue factor. Once this is accomplished, radioimmunoassays will be developed for this substance.
| Hathcock, James; Rusinova, Elena; Vaananen, Heikki et al. (2007) Lipid-bound factor Xa regulates tissue factor activity. Biochemistry 46:6134-40 |
| Jesty, Jolyon; Rodriguez, Jose; Beltrami, Edward (2005) Demonstration of a threshold response in a proteolytic feedback system: control of the autoactivation of factor XII. Pathophysiol Haemost Thromb 34:71-9 |
| Song, Xu; Sui, Aiwei; Garen, Alan (2004) Binding of mouse VL30 retrotransposon RNA to PSF protein induces genes repressed by PSF: effects on steroidogenesis and oncogenesis. Proc Natl Acad Sci U S A 101:621-6 |
| Hathcock, James J; Nemerson, Yale (2004) Platelet deposition inhibits tissue factor activity: in vitro clots are impermeable to factor Xa. Blood 104:123-7 |
| Schecter, Alison D; Berman, Adriane B; Yi, Lin et al. (2004) MCP-1-dependent signaling in CCR2(-/-) aortic smooth muscle cells. J Leukoc Biol 75:1079-85 |
| Kim, William J H; Chereshnev, Igor; Gazdoiu, Mihaela et al. (2003) MCP-1 deficiency is associated with reduced intimal hyperplasia after arterial injury. Biochem Biophys Res Commun 310:936-42 |
| Schecter, Alison D; Berman, Adriane B; Taubman, Mark B (2003) Chemokine receptors in vascular smooth muscle. Microcirculation 10:265-72 |
| Feinstein, Efraim; Deikus, Gintaras; Rusinova, Elena et al. (2003) Constrained analysis of fluorescence anisotropy decay:application to experimental protein dynamics. Biophys J 84:599-611 |
| Simon-Lukasik, Kristine V; Persikov, Anton V; Brodsky, Barbara et al. (2003) Fluorescence determination of tryptophan side-chain accessibility and dynamics in triple-helical collagen-like peptides. Biophys J 84:501-8 |
| Roque, Merce; Kim, William J H; Gazdoin, Michaela et al. (2002) CCR2 deficiency decreases intimal hyperplasia after arterial injury. Arterioscler Thromb Vasc Biol 22:554-9 |
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