) This application intends to complement the candidate's work in Emergency Medicine and previous Cellular research. Dr. Vanden Hoek is board certified in Emergency Medicine, appointed as Assistant Professor in the Section of Emergency Medicine, Department of Medicine at the University of Chicago. He has served as the site primary investigator in a multicenter trial regarding the rapid diagnosis of ischemic heart disease. His clinical and research backgrounds logically extend into asking how the ischemic heart can be better protected at the cellular level. Answers could improve our clinical treatment of myocardial infarction and other ischemic diseases, leading causes of death and disability. Preliminary work shows that preconditioning in cardiomyocytes, whereby brief hypoxia protects against subsequent ischemia/reperfusion injury, is mediated by reactive oxygen species (ROS). Intracellular fluorescent probes sensitive to these ROS suggest that preconditioning is initiated by ROS signaling during brief hypoxia. Subsequently, the severe ROS generation and injury typically seen during ischemia/reperfusion is attenuated by preconditioning. These protective effects are reversed when nitric oxide (NO) formation is inhibited, implicating a role for NO in preconditioning. Given these results, the applicant will (a) test if low levels of oxidants induce precondition, (b) test whether mediators of preconditioning such as adenosine, protein kinase activation, or potassium channel opening attenuate oxidant injury, and (c) will examine the role of NO in this oxidant protection. Perfused cardiomyocytes have proven useful for the study of oxidant injury and preconditioning, two ideas central to this proposal. These cells can be monitored for cell contraction, intracellular oxidants and antioxidant defenses, and cell death in a system free of confounding factors such as vascular flow, humoral and neural factors. Proposed agonists and antagonists of preconditioning can be tested for their effect on oxidant stress and injury, and levels of nitric oxide can be easily modified. The candidate has extensive physical and academic support at the University of Chicago, with his own dedicated lab space and established ongoing relationships with two senior mentors keenly interested in seeing his work succeed. In addition, he is an invited member of a faculty workgroup, The Oxidative Stress and Signaling Workgroup, which meets monthly and has already helped his growth as a reactive oxygen and cellular investigator.
