Monocytes/macrophages play key roles in inflammatory and atherosclerotic processes. Since thrombin is a potent effector of these responses, the overall hypothesis is that thrombin production at the monocyte/macrophage surface provides an important bioregulatory effector molecule at these sites. Objectives are to define binding and kinetic parameters governing molecular events resulting in expression of thrombin at the monocyte/macrophage surface and to elucidate cellular mechanisms which regulate expression of a procoagulant phenotype. This will be accomplished in six specific aims as follows. 1) The prothrombinase complex assembly function and regulation at the monocyte/macrophage surface will be defined. How this complex is modulated by membrane associated proteases, activated protein C/protein S inactivation complex, agonist activation of cells and adherence to various protein substrates, particularly laminin will be determined. 2) The procoagulant phenotype of monocytes/macrophages bound to extracellular matrix substrates such as laminin will be determined, with respect to tissue factor expression, Xa catalyzed cleavage of IX, and expression of membrane-bound proteases. 3) The integrin receptor that mediates monocyte binding to laminin will be identified and the effect of laminin receptor occupancy on procoagulant phenotype will be determined. 4) Studies to determine why IXalpha formed by Xa bound to monocytes is not a substrate for monocyte-bound TF/VIIa complex will be initiated as will studies to determine how IXalpha production by bound Xa is regulated. 5) the regions of Va and Xa that mediate independent binding to the monocyte surface will be determined. 6) Studies to define and characterize the Va receptor expressed on monocytes/macrophages will be initiated.
| Camire, R M; Kalafatis, M; Tracy, P B (1998) Proteolysis of factor V by cathepsin G and elastase indicates that cleavage at Arg1545 optimizes cofactor function by facilitating factor Xa binding. Biochemistry 37:11896-906 |
| Bouchard, B A; Shatos, M A; Tracy, P B (1997) Human brain pericytes differentially regulate expression of procoagulant enzyme complexes comprising the extrinsic pathway of blood coagulation. Arterioscler Thromb Vasc Biol 17:1-9 |
