Faculty, Graduate Program
Adjunct Professor, Department of Medicine, University of California at San Diego
The Cytoprotective Protein C Pathway
Our overall goal is to combine basic lab, preclinical studies and clinical research elements as parts of a broad interdisciplinary research program with strong translational dimensions. Studies of the multiple biologic activities of the plasma protease, activated protein C (APC), have helped to define the cytoprotective protein C pathway components and their mechanisms of action. APC is a homeostatic protease that counteracts many bodily stresses and injuries, e.g., ischemia reperfusion injury such as ischemic stroke, infections that cause sepsis, and radiation injury. Protein engineering is used to establish structure-function relationships for APC and to dissect its anticoagulant activity from its cell signaling actions. One APC mutant with selectively reduced anticoagulant activity, known as 3K3A-APC, is in clinical trials for ischemic stroke. Other APC mutants are being studied for other potential indications. Research is also focused on APC receptors, including protease activated receptor 1 (PAR1) that mediates beneficial cell signaling activities as APC activation of this GPCR exhibits a remarkable pattern of biased agonism. Genetically modified mice are used for animal injury model experiments to provide proof of concept for mechanisms underlying the protective cell signaling effects of APC and APC mutants.
Blood Proteins, Lipids, and Thrombosis
Venous and arterial thrombosis contribute to morbidity and mortality for many Americans. Our laboratory is involved in long-term studies of plasma proteins and lipids 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. Among known mechanisms, the protein C pathway plasma components provide physiologic antithrombotic activity. Current research is focused on discovery of new networks, mechanisms, and molecules that contribute to regulate the "hemostatic balance", i.e., the balance between preventing bleeding while preventing excessive blood clotting (thrombosis).
Ph.D., Biophysics, University of California, Davis, 1969
B.S., Physics, Santa Clara University, 1965
Fellow in Biological Chemistry (Elkan R. Blout lab), Harvard Medical School, 1969–1971
Senior Research Fellow (Christian B. Anfinsen Lab), NIH, 1971–1973
Staff Scientist, Service de Biochimie, Centre d'Etudes Nucleaires, Saclay, France, 1973–1974
Asst. Professor to Professor, Department of Molecular & Experimental Medicine, 1974 - present
Adjunct Professor of Medicine, University of California at San Diego, 2008 – present
RCA Physics & Santa Clara Jesuit Scholarships, 1961–65
Helen Hay Whitney Postdoctoral Fellow Award, 1969–72
NIH Research Career Development Award, 1976-81
NHLBI MERIT Award, 1994–2004
American Society Clinical Investigation, Honorary Member 1995
International Society of Thrombosis & Hemostasis: Board of Directors (Council) 1999-2004
American Heart Association: National Research Committee 2002-2005; Western States Affiliate, Vice-President for Research & Board of Directors, 1993-95.
American Society Hematology, Chair of Thrombosis & Vascular Biology Subcomm., 1999-2004
International Society on Thrombosis & Hemostasis, Career Achievement Award, 2005
Griffin JH. The thrombin paradox. Nature 378:337-338, 1995.
Cheng T, Liu D, Griffin JH, Fernandez JA, Castellino F, et al, 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. PMID: 12563316.
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(Pt 1):65-70, 2003. PMCID: PMC1223481.
Liu D, Cheng T, Guo H, Fernández JA, Griffin JH, Song X, Zlokovic BV. Tissue plasminogen activator neurovascular toxicity is controlled by activated protein C. Nature Medicine 10(12):1379-83, 2004. PubMed PMID: 15516929
Mosnier LO, Gale AJ, Yegneswaran S, Griffin JH. Activated protein C variants with normal cytoprotective but reduced anticoagulant activity. Blood. 104(6):1740-4, 2004. PMID: 15178575.
Guo H, Liu D, Gelbard H, Cheng T, Insalaco R, Fernández JA, Griffin JH, Zlokovic BV. Activated protein C prevents neuronal apoptosis via protease activated receptors 1 and 3. Neuron. 41(4):563-72, 2004. PubMed PMID: 14980205.
Deguchi H, Yegneswaran S, Griffin JH. Sphingolipids as bioactive regulators of thrombin generation. J Biol Chem, 279:12036-12042, 2004.
Cheng T, Petraglia AL, Li Z, Thiyagarajan M, Zhong Z, Wu Z, Liu D, Maggirwar SB, Deane R, Fernández JA, LaRue B, Griffin JH, Chopp M, Zlokovic BV. Activated protein C inhibits tissue plasminogen activator-induced brain hemorrhage. Nature Medicine. 12(11):1278-85, 2006. PubMed PMID: 17072311.
Mosnier LO, Zlokovic BV, Griffin JH. The cytoprotective protein C pathway. Blood. 109:3161-72, 2007. Review. PubMed PMID:17110453.
Thiyagarajan M, Fernandez JA, Lane SM, Griffin JH, & Zlokovic BV. Activated protein C promotes neovascularization and neurogenesis in postischemic brain via protease-activated receptor 1. J Neurosci 28(48):12788-12797, 2008. PMCID: PMC2742231.
Kerschen EJ, Fernandez JA, Cooley BC, Yang XV, Sood R, Mosnier LO, Castellino FJ, Mackman N, *Griffin JH, *Weiler H. Endotoxemia and sepsis mortality reduction by non-anticoagulant activated protein C. J Exper Med 204:2439-48, 2007. (*co-senior author) PMCID: PMC 2118455.
Guo H, Singh I, Wang Y, Deane R, Barrett T, Fernández JA, Chow N, Griffin JH, Zlokovic BV. Neuroprotective activities of activated protein C mutant with reduced anticoagulant activity. Eur J Neurosci 29(6):1119-1130, 2009. PMCID: PMC2692517.
Yang XV, Banerjee Y, Fernández JA, Deguchi H, Xu X, Mosnier LO, Urbanus RT, de Groot PG, White-Adams TC, McCarty OJ, Griffin JH. Activated protein C ligation of ApoER2 (LRP8) causes Dab1-dependent signaling in U937 cells. Proc Natl Acad Sci U S A. 106:274-9, 2009. PMCID: PMC2629184.
Kerschen E, Hernandez I, Zogg M, Jia S, Hessner MJ, Fernandez J, Griffin JH, Huettner CS, Castellino FJ, Weiler H. Activated protein C targets CD8+ dendritic cells to reduce the mortality of endotoxemia in mice. J Clin Invest. 20:3167-3178, 2010. PMCID: PMC2929901.
Griffin JH. Chapter 116. Control of Coagulation Reactions. In: William's Hematology 8th Edition. (Kaushansky KA et al, Eds) pp. 1845-1861, 2010.
Bir N, Lafargue M, Howard M, Goolaerts A, Roux J, Carles M, Cohen MJ, Iles KE, Fernández JA, Griffin JH, Pittet JF. Cytoprotective-selective activated protein C attenuates Pseudomonas aeruginosa-induced lung injury in mice. Am J Respir Cell Mol Biol. 45:632-41, 2011. PMCID: PMC3175583.
Zlokovic BV, Griffin JH. Cytoprotective protein C pathways and implications for stroke and neurological disorders. Trends Neurosci. 34:198-209, 2011. PMCID: PMC3491752.
Griffin JH, Zlokovic BV, Mosnier LO. Protein C anticoagulant and cytoprotective pathways. Int J Hematol. 95(4):333-45, 2012. PMID: 22477541; PubMed Central PMCID: PMC3413316.
Geiger H, Pawar SA, Kerschen EJ, Nattamai KJ, Cancelas JA, Hernandez I, Liang HP, Fernandez JA, Kustikova O, Schambach A, Fu Q, Wang J, Fink LM, Peterson KU, Zhou D,
Griffin JH, Baum C, Weiler H, Hauer-Jenson M. Pharmacological targeting of the thrombomodulin–protein C pathway mitigates radiation toxicity. Nature Medicine,18:1123-29, 2012. PMID: 22729286. PMCID: PMC3491776.
Wang Y, Zhang Z, Chow N, Davis TP, Griffin JH, Chopp M, Zlokovic, BV. An activated protein C analog with reduced anticoagulant activity extends the therapeutic window of tPA for ischemic stroke in rodents. Stroke, 43:2444-9, 2012. PMID: 22811462. PMCID: PMC3429704.
Mosnier LO, Sinha RK, Burnier L, Bouwens EA, Griffin JH. Biased agonism of protease-activated receptor 1 by activated protein C caused by noncanonical cleavage at Arg46. Blood. 120: 5237-46, 2012. PMCID: PMC3537315.
Guo H, Zhao Z, Yang Q, Wang M, Bell R, Wang S, Chow N, Davis T, Griffin JH, Goldman S, and Zlokovic BV. An activated protein C analog stimulates neuronal production by human neural progenitor cells via a PAR1-PAR3-S1PR1-Akt pathway. J Neuroscience, 33:6181-90, 2013.
PMID: 23554499; PubMed Central PMCID: PMC3707621.
Wang Y, Zhao Z, Chow N, Ali T, Griffin JH, Zlokovic BV. Activated protein C analog promotes neurogenesis and improves neurological outcome after focal ischemic stroke in mice via protease activated receptor 1. Brain Research, 1507:97-104, 2013. PMCID: PMC3739836.
von Drygalski A, Furlan-Freguia C, Ruf W, Griffin JH, Mosnier LO. Organ-specific protection against lipopolysaccharide-induced vascular leak is dependent on the endothelial protein C receptor. Arterioscler Thromb Vasc Biol. 33(4):769-76, 2013. PMCID: PMC3735365.
Guo H, Zhao Z, Yang Q, Wang M, Bell R, Wang S, Chow N, Davis T, Griffin JH, Goldman S, and Zlokovic BV. An activated protein C analog stimulates neuronal production by human neural progenitor cells via a PAR1-PAR3-S1PR1-Akt pathway. J Neuroscience, 33(14):6181-90, 2013. PMCID: PMC3707621.
Heeb MJ, Mesters RM, Fernandez JA, Hackeng TM, Nakasone RK, Griffin JH. Plasma protein S residues 37-50 mediate its binding to factor Va and inhibition of blood coagulation. Thrombosis and Haemostasis, 110(2):275-82, 2013. NIHMS478573.
Wang Y, Zhao Z, Chow N, Rajput PS, Griffin JH, Lyden PD, Zlokovic BV. (2013) Activated protein C analog protects from ischemic stroke and extends the therapeutic window of tissue-type plasminogen activator in aged female mice and hypertensive rats. Stroke 44(12):3529-3536. PMCID: PMC3912991.
Mosnier LO, Griffin JH. Protein C, protein S, thrombomodulin and endothelial protein C receptor pathways. In: Marder VJ, Aird WC, Bennett JS, Schulman S. White GC, Colman RW, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. pp. 300-313, 2013.
Lyden P, Levy H, Weymer S, Pryor K, Kramer W, Griffin JH, Davis TP, Zlokovic B. Phase 1 safety, tolerability and pharmacokinetics of 3K3A-APC in healthy adult volunteers. Curr Pharm Design. 2013;19(42):7479-85. PubMed PMID: 24372304.
Winkler EA, Sengillo JD, Sagare AP, Zhao Z, Ma Q, Zuniga E, Wang Y, Zhong Z, Sullivan JS, Griffin JH, Cleveland DW, Zlokovic BV. Blood-spinal cord barrier disruption contributes to early motor-neuron degeneration in ALS-model mice. Proc Natl Acad Sci U S A. 2014 Mar 18;111(11):E1035-42. Epub 2014 Mar 3. PubMed PMID: 24591593; PubMed Central PMCID: PMC3964055.