John Griffin, PhD

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).