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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL006350-51
Application #
8375946
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
51
Fiscal Year
2012
Total Cost
$431,324
Indirect Cost
$139,889
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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