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.
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.
|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|
|Wu, Sangwook; Beard, William A; Pedersen, Lee G et al. (2014) Structural comparison of DNA polymerase architecture suggests a nucleotide gateway to the polymerase active site. Chem Rev 114:2759-74|
|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|
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