Novel Copolymer-based Cell Membrane Stabilizers to Attenuate Myocardial Infarction

新型共聚物基细胞膜稳定剂可减轻心肌梗塞

• 批准号: 9898303
• 负责人: Matthias L. Riess
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898303
• 关键词: Affect; Anesthesiology; Apoptosis; Area; Atherosclerosis; Attenuated; Basic Science; Blood flow; Cardiac; Cardiac Myocytes; Cardiovascular system; Caring; Cell Culture Techniques; Cell Death; Cell Survival; Cell membrane; Cell physiology; Cells; Cellular Stress; Chemical Engineering; Chemical Structure; Chemicals; Clinical Research; Coculture Techniques; Complement; Complex; Coronary; Coronary Arteriosclerosis; Coronary artery; Critical Illness; Custom; Dose; Endothelial Cells; Endothelium; Family suidae; Fluorescence; Functional disorder; Gap Junctions; Heart; Hydrophobicity; Hypoxia; In Vitro; Incidence; Individual; Infarction; Infusion procedures; Injury; Interdisciplinary Study; Ischemia; Knockout Mice; Label; Lead; Link; Location; Measures; Mediating; Medical; Medicine; Membrane; Metabolic; Microscopy; Mitochondria; Modification; Molecular; Morbidity - disease rate; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthetase Inhibitor; Organ; Outcome; Oxidative Stress; Oxides; Pathologic; Patient Care; Patients; Physiology; Poloxamer 188; Polyethylene Glycols; Polypropylenes; Population; Positioning Attribute; Preparation; Prevention; Process; Property; Quality of life; Recovery of Function; Reperfusion Injury; Reperfusion Therapy; Research; Research Personnel; Research Proposals; Role; Side; Signaling Molecule; Testing; Time; Tissues; Translational Research; United States Food and Drug Administration; Veterans; Vulnerable Populations; Work; attack victim; base; cardioprotection; cell injury; clinically relevant; copolymer; design; experimental study; functional improvement; hydrophilicity; improved; in vivo; innovation; monolayer; mortality; novel; novel strategies; novel therapeutic intervention; oxidative damage; preservation; prevent; protective effect; response; seal

Project Summary / Abstract As a board-certified VA anesthesiologist and cardiovascular physiologist I study protective mechanisms against ischemia/reperfusion (IR) injury ultimately geared to help our often multi-morbid patients. Veterans frequently suffer from atherosclerosis, including coronary artery disease, and, therefore, have a high incidence of myocardial infarction, with often debilitating functional consequences if surviving. Paradoxically, abrupt reperfusion, i.e., reintroduction of blood flow after prolonged ischemia, and its concomitant molecular and metabolic changes may be more detrimental than the injury caused by the initial ischemia itself. Accordingly, our revised application focuses on mitigating myocardial IR injury by administration of known and newly designed synthetic copolymer-based cell membrane stabilizers (CCMS) given on reperfusion, and on elucidating their protective mechanisms of action. For this original area in cardiovascular research, we propose to use: 1) individual cell cultures and co-cultures of coronary artery endothelial cells and cardiomyocytes; and 2) an isolated, intact heart preparation of myocardial infarction. These will complement each other in focusing on novel mechanisms of myocardial protections by CCMS. Our inter-disciplinary research team from anesthesiology, physiology, and chemical engineering brings together expertise with a wide spectrum of scientific qualifications that combine fields of basic science and medicine that normally have minimal to no interaction in translational research. As such, we are uniquely positioned to enhance our understanding of the complex pathophysiological processes that take place during and after prolonged myocardial IR and to find innovative ways to increase survival, functional recovery and quality of life in thousands of critically ill patients each year. Thus, findings from this highly innovative project may result in novel treatments for victims of heart attacks and may have important implications on the optimal medical care for patients, especially in our vulnerable Veteran population.

项目概要/摘要 作为一名经过委员会认证的 VA 麻醉师和心血管生理学家，我研究保护机制 对抗缺血/再灌注（IR）损伤最终旨在帮助我们经常患有多种疾病的患者。退伍军人 经常患有动脉粥样硬化，包括冠状动脉疾病，因此发病率很高 心肌梗塞，如果幸存，通常会导致功能衰弱。矛盾的是，突然的 再灌注，即长时间缺血后重新引入血流，及其伴随的分子和 代谢变化可能比最初缺血本身造成的损伤更有害。因此， 我们修订后的申请重点是通过施用已知和新的药物来减轻心肌 IR 损伤 设计了基于合成共聚物的细胞膜稳定剂（CCMS），用于再灌注和 阐明其保护作用机制。对于心血管研究的这个原始领域，我们 建议使用：1）冠状动脉内皮细胞的单独细胞培养物和共培养物以及 心肌细胞； 2) 分离的、完整的心肌梗塞心脏标本。这些将补充 双方共同关注 CCMS 心肌保护的新机制。我们的跨学科 来自麻醉学、生理学和化学工程的研究团队汇集了专业知识 广泛的科学资格，结合了通常具有的基础科学和医学领域 转化研究中的互动很少甚至没有。因此，我们具有独特的优势来增强我们的 了解长时间期间和之后发生的复杂病理生理过程 心肌 IR 并寻找创新方法来提高患者的生存率、功能恢复和生活质量 每年有数千名重症患者。因此，这个高度创新项目的发现可能会导致 针对心脏病发作患者的新疗法，可能对最佳医疗护理产生重要影响 对于患者，尤其是我们脆弱的退伍军人群体。