The long-term goal of this research is to understand the controlling interactions among key enzymes in the blood coagulation system. It is hoped that information derived from these studies will help improve treatments for, not only individuals with bleeding disorders, but also for those affected by the broader health problem, thrombosis. To accomplish these goals the studies will include the following specific research aims: 1) identify any cofactors or other accessory proteins that collaborate with vitamin K epoxide reductase in producing vitamin K hydroquinone;2) investigate the structural elements controlling factor IX interactions with collagen IV and its role in coagulation;and 3) characterize the mechanism by which pharmacologic doses of factor Vila restore hemostasis.
These aims will be achieved by using multifaceted approaches ranging from basic biochemistry and molecular biology to animal models. Studies will employ molecular biology, tissue culture, and biochemical methods to investigate the interaction of vitamin K epoxide reductase with other cellular proteins. Similar molecular biology and tissue culture methods will be used to create coagulation factor IX and factor VII variants which will be evaluated in a variety of model systems including a cell-based coagulation model and animal models including factor IX deficient mice and mice with factor IX that does not bind collagen IV. In vivo effects of these molecules will be evaluated by intravital microscopy.

Public Health Relevance

We believe the research proposed will lead to better therapeutic methods for treating the multi-facet disorders affecting the blood clotting system. These disorders, including heart attack and stroke, are the leading cause death in western countries including the United States.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Chapel Hill
United States
Zip Code
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

Showing the most recent 10 out of 28 publications