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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Link, Rebecca P
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Bode, Michael; Mackman, Nigel (2014) Regulation of tissue factor gene expression in monocytes and endothelial cells: Thromboxane A2 as a new player. Vascul Pharmacol 62:57-62
Parker, Christine H; Morgan, Christopher R; Rand, Kasper D et al. (2014) A conformational investigation of propeptide binding to the integral membrane protein ?-glutamyl carboxylase using nanodisc hydrogen exchange mass spectrometry. Biochemistry 53:1511-20
Feng, D; Stafford, K A; Broze, G J et al. (2013) Evidence of clinically significant extravascular stores of factor IX. J Thromb Haemost 11:2176-8
Owens 3rd, A Phillip; Mackman, Nigel (2012) Sources of tissue factor that contribute to thrombosis after rupture of an atherosclerotic plaque. Thromb Res 129 Suppl 2:S30-3
Owens 3rd, A Phillip; Passam, Freda H; Antoniak, Silvio et al. (2012) Monocyte tissue factor-dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin. J Clin Invest 122:558-68
Wu, Sangwook; Liu, Shubin; Davis, Charles H et al. (2011) A hetero-dimer model for concerted action of vitamin K carboxylase and vitamin K reductase in vitamin K cycle. J Theor Biol 279:143-9
Owens 3rd, A Phillip; Mackman, Nigel (2011) Microparticles in hemostasis and thrombosis. Circ Res 108:1284-97
Monroe, Dougald M; Mackman, Nigel; Hoffman, Maureane (2010) Wound healing in hemophilia B mice and low tissue factor mice. Thromb Res 125 Suppl 1:S74-7
Mackman, Nigel; Becker, Richard C (2010) DVT: a new era in anticoagulant therapy. Arterioscler Thromb Vasc Biol 30:369-71
de Courcy, B; Pedersen, L G; Parisel, O et al. (2010) Understanding selectivity of hard and soft metal cations within biological systems using the subvalence concept. I. Application to blood coagulation: direct cation-protein electronic effects vs. indirect interactions through water networks. J Chem Theory Comput 6:1048-1063

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