PROJECT SUMMARY/ABSTRACT Myocardial infarction is induced by an ischemic event and often leads to damage of the myocardium and potentially death. The primary clinical goal during treatment of myocardial infarction is to restore blood flow to the myocardium as quickly as possible. However, paradoxically, the reperfusion can cause significant damage to the myocardium. Of the total infarcted volume, potentially up to 50% can be attributed to reperfusion and not ischemia. The reperfusion injury occurs, in part, due to the ischemic tissue converting the newfound supply of oxygen into reactive oxygen species. Reactive oxygen species can significantly damage a cell and lead to cell death. This career development award (CDA) takes advantage of the principal investigator's quantitative background in ultrasound physics, signal processing, and cavitation to develop a novel approach to inhibiting reperfusion injury. The technique relies on a process known as acoustic droplet vaporization, where a liquid droplet is phase-transitioned into a gas microbubble when exposed to ultrasound. The microbubble acts a sink for dissolved oxygen in whole blood, effectively sequestering the oxygen within the microbubble so that the oxygen cannot diffuse into the tissue. Our central hypothesis is that ultrasound-mediated oxygen scavenging during reperfusion, following an ischemic event, increases cell and tissue viability. This hypothesis will be tested through studies focusing on the efficiency and efficacy of oxygen scavenging in vitro, ex vivo, and in vivo. The first aim of this CDA is to understand how the efficiency of oxygen scavenging varies based the composition of the droplets. Next, a series of experiments will be performed to measure the reactive oxygen species production and cell death in cell culture, isolated whole heart with Langendorff preparation, and finally in vivo. The progression of these experiments will ensure a thorough understanding of the therapy and how modifications to the approach can be made to improve therapeutic efficacy. In the process of carrying out these aims, the PI will undergo mentored research training to develop skills that will enable the PI to take future basic science discoveries in ultrasound physics and advance them towards cardiovascular application in humans. In particular, the PI will develop a working expertise of oxygen transport, cardiovascular physiology, ischemia-reperfusion injury, the selection, implementation, and analysis of relevant animal models, and the design of translatable ultrasound systems. Didactic coursework, independent study, and hands-on experiential learning will form the bulk of the training techniques used. The CDA has been carefully designed to supplement the PI's extensive quantitative background to enable him to successfully build an independent research program focused on the treatment of cardiovascular diseases.

PROJECT NARRATIVE While new therapies to restore blood flow can be life-saving, up to half of the volume of heart tissue at risk during a heart attack dies, paradoxically, due to the return of blood flow. The previously oxygen-starved heart muscle responds to the influx of oxygen by creating free radicals that damage the patient's heart cells, so- called reperfusion injury. This project uses a novel, ultrasound-based technique to sequester oxygen from the blood to limit free radical formation and reduce reperfusion injury.