Scripps Research Joint Appointments

Center for Integrative Molecular Biosciences
Faculty, Kellogg School of Science and Technology

Research Focus

Thrombosis, Blood Coagulation and the Antithrombotic Protein C Pathway

Venous and arterial thrombosis contribute to morbidity and mortality for many Americans. Our laboratory is involved in long-term studies of plasma proteins that regulate thrombosis and hemostasis. Networks of mechanisms for up-regulation and down-regulation of thrombin generation or of other coagulation factor proteases must act in concert to prevent bleeding and yet avoid harmful blood clots. The protein C pathway's key enzyme, activated protein C, provides physiologic antithrombotic activity and remarkably also exhibits both anti-inflammatory and anti-apoptotic activities. Biochemical, molecular biological, and clinical research studies contribute to the laboratory's interdisciplinary approach to define molecular mechanisms or defects that are related to development of thrombosis and ischemic stroke. Animal model experiments and clinical research studies are employed to assess the physiologic or pathologic significance of molecular mechanisms that are defined in vitro using purified proteins. Protein engineering is used to establish structure-function relationships for clotting factors. Using biochemical and clinical studies of plasma lipids and lipoproteins, the laboratory is defining the influences of lipids and lipoproteins that modulate coagulation and protein C pathways because of the strong epidemiologic association between hyperlipidemia and hypercoagulability. The goal of our research is to engage fully in research that extends from bench to bedside.

Education

Ph.D., University of California, Davis, 1969

Awards & Professional Activities

Member, Research Policy Committee, American Heart Association; Honorary Member, American Society for Clinical Investigation; Member, International Society on Thrombosis & Hemostasis Council; Editorial Board, Arteriosclerosis, Thrombosis, and Vascular Biology.

Selected References

Cheng T, Liu D, Griffin JH, Fernandez JA, Castellino F, Rosen ED, Fukudome K, Zlokovic BV. Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective in a murine stroke model through EPCR and PAR-1. Nature Medicine, 9:338-342, 2003.

Mosnier LO, Griffin JH. Inhibition of staurosporine-induced apoptosis of endothelial cells by activated protein C requires protease activated receptor-1 and endothelial cell protein C receptor. Biochem J., 373:65-70, 2003.

Gale AJ, Griffin JH. Characterization of a thrombomodulin binding site on protein C and its comparison to an activated protein C binding site for factor Va. Proteins: Structure, Function, and Bioinformatics, 54:433-441, 2004.

Deguchi H, Yegneswaran S, Griffin JH. Sphingolipids as bioactive regulators of thrombin generation. J. Biol. Chem., 279:12036-12042, 2004.