Abstract

Activated protein C is a potent inhibitor of blood coagulation. Defects in protein C and the proteins that regulate its activity may lead to the development of thrombosis. The long term goal of this project is to determine the molecular basis of the action of protein C and the mechanisms of its regulation. The purpose of this project is to study the mechanisms by which protein S, a cofactor for activated protein C, is regulated.
The first aim of the research is to characterize the proteins in plasma and formed elements of blood that interest with protein S. This will involve isolation of these proteins by standard chromatographic methods and determination the relationship between the proteins through sequence analysis and immunochemistry. Secondly, the functional significance of the proteins will be ascertained by determining the concentrations of the components and the affinities between the binding proteins and protein S. In addition the effects of these proteins on the anticoagulant activity of activated protein C will be determined.
The third aim of the project is to study the relationship between protein S primary structure and the functional properties of the protein. This will be carried out by studies of peptides found in the protein S sequence, chemical modification experiments and characterization of the functional properties of chemically modified protein S.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL040328-04
Application #
3357453
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1988-08-01
Project End
1993-07-31
Budget Start
1991-08-15
Budget End
1992-07-31
Support Year
4
Fiscal Year
1991
Total Cost
Indirect Cost

  Institution

Name
American National Red Cross Connecticut
Department
Type
DUNS #
City
Farmington
State
CT
Country
United States
Zip Code
06032

  Publications

Regan, L M; Lamphear, B J; Huggins, C F et al. (1994) Factor IXa protects factor VIIIa from activated protein C. Factor IXa inhibits activated protein C-catalyzed cleavage of factor VIIIa at Arg562. J Biol Chem 269:9445-52
Weinstein, R E; Walker, F J (1993) Effect of rabbit activated protein C on thrombin generation and fibrinolysis in a species-specific in vivo model: effect of modulation of protein S activity. Semin Thromb Hemost 19:368-77
Walker, F J (1992) Characterization of the interaction between the heavy and light chains of bovine factor Va. J Biol Chem 267:19896-900
Parke, A L; Weinstein, R E; Bona, R D et al. (1992) The thrombotic diathesis associated with the presence of phospholipid antibodies may be due to low levels of free protein S. Am J Med 93:49-56
Fay, P J; Coumans, J V; Walker, F J (1991) von Willebrand factor mediates protection of factor VIII from activated protein C-catalyzed inactivation. J Biol Chem 266:2172-7
Weinstein, R E; Walker, F J (1991) Species specificity of the fibrinolytic effects of activated protein C. Thromb Res 63:123-31
Fay, P J; Smudzin, T M; Walker, F J (1991) Activated protein C-catalyzed inactivation of human factor VIII and factor VIIIa. Identification of cleavage sites and correlation of proteolysis with cofactor activity. J Biol Chem 266:20139-45
Walker, F J (1990) Protein C deficiency in liver disease. Ann Clin Lab Sci 20:106-12
Weinstein, R E; Walker, F J (1990) Enhancement of rabbit protein S anticoagulant cofactor activity in vivo by modulation of the protein S C4B binding protein interaction. J Clin Invest 86:1928-35
Walker, F J; Scandella, D; Fay, P J (1990) Identification of the binding site for activated protein C on the light chain of factors V and VIII. J Biol Chem 265:1484-9

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