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: 10265405
• 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 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265405
• 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; 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; military veteran; 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.

项目摘要/摘要 作为委员会认证的退伍军人管理局麻醉师和心血管生理学家，我研究保护机制 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 心肌梗死，如果存活下来，往往会导致虚弱的功能后果。矛盾的，突然的 再灌注，即长时间缺血后血流的重新输入，及其伴随的分子和 新陈代谢的变化可能比最初的缺血本身造成的损伤更有害。因此， 我们修订的应用侧重于通过给药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)，用于再灌注等 阐明其保护作用机制。对于心血管研究的这一原创领域，我们 建议使用：1)冠状动脉内皮细胞单独培养和共培养 心肌细胞；以及2)心肌梗死的分离、完整的心脏制剂。这些将相辅相成 共同关注CCMS保护心肌的新机制。我们的跨学科 来自麻醉学、生理学和化学工程学的研究团队将专业知识与 广泛的科学资格证书，结合了基础科学和医学领域，这些领域通常有 翻译研究中的互动很少，甚至没有。因此，我们处于独特的地位，可以增强我们的 对在延长期间和之后发生的复杂的病理生理过程的理解 并寻找提高存活、功能恢复和生活质量的创新方法 每年数以千计的危重病人。因此，这个极具创新性的项目的发现可能会导致 对心脏病患者的新治疗方法，并可能对最佳医疗保健具有重要意义 对于病人，特别是在我们脆弱的退伍军人群体中。