Ultrasound-mediated oxygen scavenging for inhibition of reperfusion injury

超声介导的氧清除抑制再灌注损伤

• 批准号: 9319306
• 负责人: Kevin Joseph Haworth
• 金额: $ 15.85万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9319306
• 关键词: Acoustics; Active Learning; Acute myocardial infarction; Alpha Cell; Animal Model; Anterior Descending Coronary Artery; Applications Grants; Award; Base Composition; Basic Science; Blood; Blood Vessels; Blood capillaries; Blood flow; Caliber; Cardiac Myocytes; Cardiac Volume; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Catheters; Cell Culture Techniques; Cell Death; Cell Survival; Cells; Cessation of life; Clinic; Clinical; Clinical Trials; Coronary; Data; Development; Diffuse; Disease; Distal; Doctor of Philosophy; Dose; Emergency Situation; Emulsions; Ensure; Event; Feasibility Studies; Fluorocarbons; Free Radical Formation; Free Radicals; Future; Gases; Goals; Heart; Hemoglobin; Human; In Vitro; Infarction; Inflammatory; Ischemia; K-Series Research Career Programs; Kinetics; Knowledge; Lead; Left; Life; Ligation; Liquid substance; Measures; Mechanical Stress; Mediating; Mentors; Methods; Microbubbles; Modeling; Modification; Myocardial Infarction; Myocardium; New Zealand; Oryctolagus cuniculus; Outcome; Oxidative Stress; Oxygen; Partial Pressure; Patients; Phase Transition; Physics; Physiologic pulse; Physiological; Plasma; Positioning Attribute; Preparation; Principal Investigator; Procedures; Process; Production; Reactive Oxygen Species; Reperfusion Injury; Reperfusion Therapy; Research; Research Training; Risk; Saline; Savings; Scientist; Series; Source; Stress; System; Techniques; Testing; Therapeutic Embolization; Tissue Viability; Tissues; Training; Training Technics; Translating; Translational Research; Translations; Treatment Efficacy; Ultrasonography; United States National Institutes of Health; Whole Blood; Work; animal model selection; base; capillary; cytokine; design; experimental study; heart cell; hemodynamics; improved; in vivo; model design; novel; novel strategies; novel therapeutics; oxygen transport; percutaneous coronary intervention; programs; signal processing; skills; vapor; vaporization

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.

项目摘要/摘要 心肌梗死是由缺血事件引起的，通常会导致心肌和 可能会死亡。治疗心肌梗死的主要临床目标是恢复血流到 尽可能快地恢复心肌。然而，矛盾的是，再灌流可能会造成重大损害。 对心肌的影响。在总的梗死体积中，可能高达50%可归因于再灌注和 不是缺血。再灌注损伤的发生，部分是由于缺血组织将新发现的补给转化为 将氧转化为活性氧物种。活性氧物种会严重损害细胞并导致 细胞死亡。该职业发展奖(CDA)利用首席调查员的量化 超声波物理、信号处理和空化背景，开发抑制的新方法 再灌注损伤。这项技术依赖于一种被称为声波液滴蒸发的过程，在这种过程中，液体 当接触到超声波时，液滴会转变为气体微泡。微泡起到水槽的作用。 对于全血中的溶解氧，有效地隔离微泡内的氧气，从而 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 在缺血事件后的再灌流期间，增加细胞和组织的存活率。这一假设将是 通过集中在体外、体外和体内清除氧气的效率和效果的研究进行测试 活着。这项CDA的第一个目标是了解氧气清除效率是如何基于 液滴的组成。接下来，将进行一系列的实验来测量活性氧 在细胞培养中产生物种和细胞死亡，用朗宁多夫制剂分离整个心脏，最后 在活体内。这些实验的进展将确保彻底了解治疗方法以及如何 可以对该入路进行修改，以提高治疗效果。在开展的过程中 为了实现这些目标，PI将接受有指导的研究培训，以发展使PI能够在未来 超声物理学的基础科学发现及其在心血管领域的应用 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，以及 可平移超声系统的设计。讲授课程、自主学习和亲身体验 学习将构成所使用的大部分训练技术。CDA经过精心设计，以 补充PI广泛的量化背景，使他能够成功构建独立的 研究项目的重点是心血管疾病的治疗。