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 心肌梗死是由缺血性事件引起的，通常会导致心肌损坏 潜在的死亡。在治疗心肌梗塞期间的主要临床目标是恢复血液流动 心肌尽快。但是，自相矛盾的是，再灌注会造成重大损害 到心肌。在总梗塞数量中，可能高达50％的人可以归因于再灌注和 不是缺血。再灌注损伤部分是由于缺血组织转化了新发现的供应 氧成活性氧。活性氧可能会显着损害细胞，并导致 细胞死亡。该职业发展奖（CDA）利用了主要研究者的定量 超声物理，信号处理和空化的背景，以开发一种新型方法来抑制 再灌注损伤。该技术依赖于一种称为声滴汽化的过程，其中液体 当暴露于超声波时，液滴将液滴转移到气体微泡中。微泡起作水槽 对于全血中溶解的氧气，有效地隔离了微泡中的氧气，以便 氧气无法扩散到组织中。我们的中心假设是超声介导的氧气清除 在再灌注过程中，缺血事件会增加细胞和组织活力。这个假设将是 通过研究侧重于氧气在体外清除氧气的效率和功效的研究测试 体内。该CDA的第一个目的是了解氧气清除的效率如何不同 液滴的组成。接下来，将进行一系列实验以测量活性氧 细胞培养中的物种产生和细胞死亡，用兰多多夫制备孤立的全心，最后 体内。这些实验的进展将确保对治疗以及如何对 可以对方法进行修改以提高治疗功效。在执行 这些目的，PI将接受指导的研究培训，以发展技能，使PI能够采用未来 超声物理学中的基础科学发现，并将其推向心血管应用 人类。特别是，PI将开发出氧运输，心血管生理学的工作专业知识， 相关动物模型的缺血再灌注损伤，选择，实施和分析以及 可翻译超声系统的设计。教学课程，独立研究和动手体验 学习将构成所使用的大部分培训技术。 CDA经过精心设计 补充PI的广泛定量背景，使他能够成功建立独立 研究计划的重点是治疗心血管疾病。