Directory | Contact | Careers | Intranet | Home

Research Focus

Molecular Interactions and Functions of
Coagulation Cofactors Va and VIIIa

Our lab is interested in structure function relationships in proteins of the coagulation pathway. We utilize molecular biology, biochemistry and computer modeling to investigate protein-protein interactions and functional properties of coagulation factors. Additionally, we hope to utilize this knowledge to direct protein engineering with the purpose of creating altered coagulation factors that could provide improved therapeutic benefit. We have focused on the anticoagulant activated protein C (APC) pathway and the coagulation cofactors, factor Va (FVa) and factor VIIIa (FVIIIa), which APC inactivates. As a member of the Griffin laboratory, I analyzed the interactions of APC with FVa and modeled the FVa structure and the APC/FVa interaction. Our current focus is on FVIII. Deficiency of factor VIII is responsible for the hemorrhagic bleeding disorder hemophilia A. We have created recombinant variants of FVIII that yield activated FVIII with increased functional stability which could result in improved therapeutic agents for treatment of hemophilia A. We are working with these FVIII variants to define their in vitro characteristics, which relate directly to their potential as therapeutic agents, and further, to characterize their in vivo function in a mouse hemophilia model.

Education

B.A., Biology, Bethel College, 1988
Ph.D., Biology, Massachusetts Institute of Technology, 1995

Awards & Professional Activities

Early Career Investigator Award - Bayer Hemophilia Awards Program.
Career Development Award -National Hemophilia Foundation.
Member, American Society of Hematology.
Member, International Society on Thrombosis and Haemostasis.

Selected References

Gale, AJ, Heeb, MJ, Griffin, JH. The Autolysis Loop of Activated Protein C Interacts with Factor Va and Differentiates Between the Arg506 and Arg306 Cleavage Sites. Blood 96:585-593, 2000.

Gale, AJ, Xu, X, Pellequer, J-L, Getzoff, ED, Griffin, JH., Interdomain Engineered Disulfide Bond Permitting Elucidation of Mechanisms of Inactivation of Coagulation Factor Va by Activated Protein C. Protein Science 11:2091-2101, 2002.

Gale, AJ, Pellequer J-L. An engineered interdomain disulfide bond stabilizes human blood coagulation factor VIIIa. Journal of Thrombosis and Haemostasis 1:1966-1971, 2003.

Radtke, K-P, Griffin, JH, Riceberg, J, Gale, AJ. Disulfide bond-stabilized factor VIII has prolonged factor VIIIa activity and improved potency in whole blood clotting assays. J Thromb Haemost, 5:102-108, 2007.

Gale, AJ, Cramer, TJ, Rozenshteyn, D, Cruz, JR.  Detailed mechanisms of the inactivation of factor VIIIa by activated protein C and its cofactors, protein S and factor V.  J Biol Chem, 283:16355-62, 2008.

Cramer, TJ, Griffin, JH, Gale, AJ, Factor V is an anticoagulant cofactor for activated protein C during inactivation of factor Va. Pathophysiology of Haemostasis and Thrombosis, 37:17-23, 2010.

Links

Gale Website

All the King’s Horses and All the King’s Men

Factor Foundation Supports Scripps Research