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. The overall goal of this research is a better understanding of coagulation in normal and diseased states

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL006350-50
Application #
8082748
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Link, Rebecca P
Project Start
1997-01-01
Project End
2014-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
50
Fiscal Year
2011
Total Cost
$1,152,076
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pathology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Boulaftali, Yacine; Owens 3rd, A Phillip; Beale, Ashley et al. (2016) CalDAG-GEFI Deficiency Reduces Atherosclerotic Lesion Development in Mice. Arterioscler Thromb Vasc Biol 36:792-9
Bode, Michael F; Mackman, Nigel (2016) A combined deficiency of tissue factor and PAR-4 is associated with fatal pulmonary hemorrhage in mice. Thromb Res 146:46-50
Owens 3rd, A Phillip; Edwards, Todd L; Antoniak, Silvio et al. (2015) Platelet Inhibitors Reduce Rupture in a Mouse Model of Established Abdominal Aortic Aneurysm. Arterioscler Thromb Vasc Biol 35:2032-2041
Wu, Sangwook; Lee, Chang Jun; Pedersen, Lee G (2014) Analysis on long-range residue-residue communication using molecular dynamics. Proteins 82:2896-2901
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
Perera, Lalith; Beard, William A; Pedersen, Lee G et al. (2014) Applications of quantum mechanical/molecular mechanical methods to the chemical insertion step of DNA and RNA polymerization. Adv Protein Chem Struct Biol 97:83-113
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
Boulaftali, Yacine; Hess, Paul R; Getz, Todd M et al. (2013) Platelet ITAM signaling is critical for vascular integrity in inflammation. J Clin Invest 123:908-16
Mutoh, Shingo; Sobhany, Mack; Moore, Rick et al. (2013) Phenobarbital indirectly activates the constitutive active androstane receptor (CAR) by inhibition of epidermal growth factor receptor signaling. Sci Signal 6:ra31
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

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