DESCRIPTION (provided by applicant): Background Platelet activation and recruitment are critical for thrombus formation and blood vessel occlusion in the vasculature, occurring in thrombotic emergencies including acute coronary syndromes (ACS), stroke, Deep Vein Thrombosis (DVT), and Pulmonary Embolus (PE). Thrombotic emergencies contribute greatly to morbidity and mortality in the U.S. There are well-characterized platelet surface receptors initiating intracellular signal transduction events which trigger platelet activation and thrombus formation. Some of these receptors are exploited clinically using anti-platelet medications for patients who experience a myocardial infarction (MI). Aspirin and clopidogrel are two anti-platelet agents used to treat MI yet one prospective study showed only a 20% reduction in adverse vascular events with the addition of clopidogrel to aspirin. During an acute MI, coronary arteries can be opened using stents. Recent data indicates that stenting a coronary artery-even with clopidogrel and aspirin therapy-leads to a `no reflow' phenomenon in around 50% of patients. No reflow, even after removing luminal obstruction, is thought to involve downstream microvascular obstruction-a region where platelets are most active. Failure of anti-platelet medications and observing no reflow sometimes leads clinicians to reflexively increase the existing drug dose, to combine anti-platelet medications, or to search for new medications against the same platelet receptors in the hope of seeing enhanced efficacy. Innovative Observation Another strategy may be to consider that platelet activity is somehow different (dysregulated) in disease conditions such as no reflow and diabetes where traditional anti-platelet medications can have unpredictable effects. In the ischemic microvasculature, platelets are exposed to enriched concentrations of reactive oxygen species (ROS) which can activate platelets independent of surface receptors. We have, for the first time, identified a protein in platelets called ERK5. ERK5 is exquisitely sensitive to ROS, and appears to act as a platelet ischemic sensor, which triggers maladaptive platelet behavior. ERK5 is a Mitogen-Activated Protein Kinase (MAPK) family member usually found in proliferating cells because it drives cell cycle progression. In the anucleate platelet, we found that ERK5 is important for normal platelet activation as well as platelet activation in response to ROS. Using a mouse MI model in which ROS and platelet activators are greatly elevated, platelet specific ERK5-/- mice have reduced infarct size and improved heart function. In addition, the expression and ubiquitination of proteins important for platelet activation are dramatically altered, suggesting there may be a switch which transforms platelets into a dysregulated state in inflammatory, post-infarct environment. Importance of the Mentored Research Award I treat patients with cardiovascular disorders and so I am acutely...