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: 10612331
• 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/10612331
• 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.

项目总结/摘要 作为一名委员会认证的VA麻醉师和心血管生理学家，我研究保护机制 针对缺血/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，具有高发病率 心肌梗死，如果存活，通常会导致功能衰弱。偶然的，突然的 再灌注，即，长时间缺血后血流的重新引入，及其伴随的分子和 代谢变化可能比初始局部缺血本身引起的损伤更有害。因此，委员会认为， 我们修改后的申请集中于通过给予已知的和新的 设计的基于合成共聚物的细胞膜稳定剂（CCMS）用于再灌注， 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 建议用途：1）冠状动脉内皮细胞的单个细胞培养物和共培养物， 心肌细胞;和2）心肌梗死的分离的完整心脏制备物。这些将补充 彼此关注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，结合联合收割机领域的基础科学和医学，通常有 翻译研究中的互动极少甚至没有。因此，我们处于独特的地位，以提高我们的 了解发生在长期的， 心肌IR和寻找创新的方法，以提高生存，功能恢复和生活质量， 每年有数千名重症患者。因此，这个高度创新的项目的结果可能会导致 为心脏病患者提供新的治疗方法，并可能对最佳医疗保健产生重要影响。 特别是在我们脆弱的退伍军人群体中。

项目成果

Potential Effects of Poloxamer 188 on Rat Isolated Brain Mitochondria after Oxidative Stress In Vivo and In Vitro.

• DOI: 10.3390/brainsci11010122
• 发表时间: 2021-01-18
• 期刊: Brain sciences
• 影响因子: 3.3
• 作者: Pille JA;Riess ML
• 通讯作者: Riess ML

Perioperative implications of patients with alpha gal allergies.

• DOI: 10.1016/j.jclinane.2023.111056
• 发表时间: 2023-01
• 期刊: Journal of clinical anesthesia
• 影响因子: 6.7
• 作者: M. Nourian;C. Stone;Kara K. Siegrist;M. Riess

Poloxamer 188 Exerts Direct Protective Effects on Mouse Brain Microvascular Endothelial Cells in an In Vitro Traumatic Brain Injury Model.

洛沙敏188在体外创伤性脑损伤模型中对小鼠脑微血管内皮细胞产生直接保护作用。

• DOI: 10.3390/biomedicines9081043
• 发表时间: 2021-08-19
• 期刊: Biomedicines
• 影响因子: 4.7
• 作者: Lotze FP;Riess ML
• 通讯作者: Riess ML

Sounds Impossible, but It's Knot.

听起来不可能，但它是结。

• DOI: 10.1097/aln.0000000000002585
• 发表时间: 2019
• 期刊: Anesthesiology
• 影响因子: 8.8
• 作者: Smith,LorenE;Heath,DillonR;Riess,MatthiasL
• 通讯作者: Riess,MatthiasL

No Direct Postconditioning Effect of Poloxamer 188 on Mitochondrial Function after Ischemia Reperfusion Injury in Rat Isolated Hearts.

• DOI: 10.3390/ijms22094879
• 发表时间: 2021-05-05
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Eskaf J;Cleveland WJ;Riess ML
• 通讯作者: Riess ML