The objectives of this investigation are to define the contribution of warfarin treatment and of dietary vitamin K deficiency to the arterial calcification process in humans and in a rat model of the disease. The Principal Investigator will assess the molecular mechanism by which matrix Gla proteins, which are vitamin K dependent, can inhibit the arterial calcification process. The applicant will identify those risk factors which act synergistically with warfarin to accelerate arterial calcification in a rat model. He will establish the extent to which arterial calcification is arrested or reversed. Within the context of this specific aim, he will investigate the effect of dietary deficiency on the carboxylation of the Gla protein and the calcification in arteries in the rat. Dr. Price will also determine the effect of warfarin on the calcification of the intima in animal models of atherosclerosis and investigate the ability of the Gla protein infusion the arterial calcification that is induced by warfarin.
The second aim, is designed to investigate the relationship between defective carboxylation of serum Gla protein and arterial calcification using isoelectric focusing and terminal protein sequencing; mineral binding activity will be done to measure carboxylation status. He will also look at the structure and functional associations of Gla protein and calcification sites in the human artery. The principal investigator will also investigate the mechanism by which the Gla proteins inhibit the calcification of elastin in the human aortic media when elastin is added to solutions that contain physiological concentrations of calcium and phosphate. He will also determine the role of Gla protein as an inhibitor of the growth of crystallites isolated by the human aortic media. These experiments are being done to establish the importance of vitamin K deficiency and of warfarin treatment as risk factors for the calcification of human arteries.
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