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 aware of the limitations and needs of currently available therapeutics. Traditionally, hematologists have contributed to platelet research while cardiologists typically prescribe anti-platelet medications.
I aim operate at the interface of basi thrombosis research and clinical cardiovascular care. There has been little advance in the development of platelet inhibiting drugs to use in patients with heart attack and I feel this is because dysregulated platelet function is not understood. I propose to mechanistically demonstrate a key role for platelet ERK5 as an `ischemia sensor', a mediator of dysregulated platelet activity following MI, and a potentially new drug target for thrombotic emergencies. The preliminary data for this study represents a significant technological advancement in terms of defining platelet function following MI as well as suggesting new relevant platelet targets for drug therapy.
The aim to use the mentored career scientist award to focus and to develop independent lines of investigation needed to launch a career as a physician scientist. To achieve this goal I will aim to characterize the mechanism by which ERK5 regulates platelet activation in the body following an ischemic insult. This will allow me to learn animal models of disease previously inaccessible to me and to complement my previous training in biochemistry and cellular signaling in a cohesive and organized manner.
Heart attack (myocardial infarction) and cerebrovascular accidents (stroke) are significant causes of morbidity and mortality in the Western world and are an enormous burden on society based on cost and loss of quality life years. Blood clotting inside the body (thrombosis) precedes heart attacks and strokes. This project has identified a new molecule that may affect thrombosis and so heart attacks. Blocking this molecule appears to markedly improve the function of the heart after a heart attack, and may also be useful in treating strokes.
