Ultrasound-mediated oxygen scavenging for inhibition of reperfusion injury

项目概要/摘要 心肌梗塞由缺血事件引起，并且通常导致心肌损伤， 可能死亡。治疗心肌梗死的主要临床目标是恢复血流， 尽快切除心肌然而，矛盾的是，再灌注会导致严重的损伤， 到心肌。在总梗死体积中，可能高达50%可归因于再灌注， 而不是局部缺血再灌注损伤的发生，部分是由于缺血组织将新发现的供应转化为 转化为活性氧活性氧物质可显著损害细胞并导致 细胞死亡这个职业发展奖（CDA）利用了首席研究员的定量研究， 在超声物理学，信号处理和空化背景，以开发一种新的方法来抑制 再灌注损伤该技术依赖于一种被称为声学液滴蒸发的过程， 当暴露于超声时，液滴相变成气体微泡。微泡起到了水槽的作用 对于全血中的溶解氧，有效地将氧气隔离在微泡内，以便 氧气不能扩散到组织中。我们的中心假设是超声波介导的氧清除 在缺血事件之后的再灌注期间，增加细胞和组织的活力。这一假设将是 通过集中于体外、离体和体内氧清除的效率和功效的研究进行测试， vivo.该CDA的第一个目的是了解氧清除效率如何基于 液滴的组成。接下来，将进行一系列实验来测量活性氧 细胞培养中的物种产生和细胞死亡，用Langendorff制备分离的整个心脏，最后 in vivo.这些实验的进展将确保彻底了解治疗和如何 可以对该方法进行修改以提高治疗效果。实施过程中 为了实现这些目标，PI将接受指导性的研究培训，以发展使PI能够在未来 超声物理学的基础科学发现，并将其推向心血管应用， 人类特别是，PI将发展氧气运输，心血管生理学， 缺血-再灌注损伤，相关动物模型的选择、实施和分析， 可平移超声系统的设计。教学课程，独立学习和动手体验 学习将成为训练技巧的主要部分。CDA经过精心设计， 补充PI广泛的定量背景，使他能够成功地建立一个独立的 研究计划集中在心血管疾病的治疗。

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.