Colin Greineder, MD, PhD
University of Michigan
"Resuscitating the Endothelial Protein C Pathway Post-Cardiac Arrest"
SAEMF Research Large Project Grant
Sudden cardiac arrest (CA) is a major health concern that affects more than 400,000 patients per year in the United States alone. In-hospital mortality remains > 50% even when return of spontaneous circulation (ROSC) is achieved, in part due to the complexity of the pathophysiology which develops after successful resuscitation. Improved understanding of the post-cardiac arrest syndrome and the development of pharmacologic agents capable of halting or reversing its pathogenesis represent major unmet medical needs. The current proposal involves a novel class of targeted therapeutics, which boost the endothelial protein C pathway, a key regulator of coagulation, fibrinolysis, and vascular barrier function. This homeostatic system is suppressed due to loss of the key endothelial surface protein, thrombomodulin (TM), which in turn leads to impaired activation of protein C. Unlike direct infusion of recombinant activated protein C, a drug previously FDA approved for the treatment of severe sepsis but plagued by poor pharmacokinetics and life-threatening toxicity, our approach directly reverses the underlying endothelial abnormality by anchoring recombinant TM to ICAM-1 on activated endothelial cells. ICAM-targeted TM restores normal protein C activation in vitro and has demonstrated efficacy in both a mouse model of ARDS and a microfluidic whole blood model of human inflammatory thrombosis. The central hypothesis of this project is that loss of endothelial TM results in dysregulated activation of coagulofibrinolytic cascades and vascular barrier disruption post-ROSC and reversal of this pathophysiology using ICAM-targeted TM will decrease organ injury after cardiac arrest. The specific aims test this hypothesis using a variety of biochemical, genetic, and pharmacologic approaches in a mouse model of CA already established at the U-M. Aim 1 will characterize coagulation, fibrinolysis, and vascular leak after CA and their correlation with markers of organ injury in both wild-type mice and those with defects in each of the functional domains of endogenous TM. Aim 2 will test the pharmacokinetics and pharmacodynamics of ICAM-targeted TM post- ROSC. Finally, Aim 3 applies this PD/PK data to determine optimal time and dosing for testing the therapeutic effects of the drug on physiologic outcomes, including pulmonary, renal, hepatic, and CNS injury/dysfunction. The ability of various pharmacodynamic biomarkers to predict drug-induced improvements in physiologic outcomes will also be determined, in preparation for future preclinical trials. The proposal brings together a mid-career EM researcher with expertise in endothelial drug delivery and the protein C pathway with established leaders in the field of CA research. The results will advance the field by providing new fundamental knowledge about the role of the protein C pathway and TM in post-cardiac arrest pathophysiology and by laying the foundation for subsequent pre-clinical and clinical trials of this translational therapeutic strategy.
Dr. Greineder is in the second year of his project.