Enhancing Cardiac Protection

加强心脏保护

• 批准号: 9339498
• 负责人: DAVID M ROTH
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9339498
• 关键词: Address; Age; Age-Years; Aging; Anesthetics; Animals; Cardiac; Cardiac Myocytes; Caveolae; Caveolins; Clinical; Data; Disease; Electron Spin Resonance Spectroscopy; Event; Female; G-Protein-Coupled Receptors; Grant; Health; Heart; Heart Diseases; Human; Imaging technology; Impairment; Ischemia; Ischemic Preconditioning; Ligands; Link; Membrane; Membrane Fluidity; Membrane Microdomains; Mitochondria; Modeling; Molecular; Molecular Biology; Molecular Biology Techniques; Morbidity - disease rate; Mus; Myocardial Ischemia; Myocardium; Patients; Pharmacologic Substance; Phosphotransferases; Physiological; Play; Population; Post-Traumatic Stress Disorders; Receptor Protein-Tyrosine Kinases; Reperfusion Injury; Reperfusion Therapy; Reporting; Research; Risk; Role; Services; Signal Transduction; Signaling Molecule; Stimulus; Techniques; Technology; Testing; Tissues; Veterans; Work; aged; agent orange; base; caveolin-3; clinically relevant; conditioning; insight; male; mortality; new therapeutic target; novel; novel therapeutics; overexpression; pre-clinical; public health relevance; response; statistics; Address; Age; Age-Years; Aging; Anesthetics; Animals; Cardiac; Cardiac Myocytes; Caveolae; Caveolins; Clinical; Data; Disease; Electron Spin Resonance Spectroscopy; Event; Female; G-Protein-Coupled Receptors; Grant; Health; Heart; Heart Diseases; Human; Imaging technology; Impairment; Ischemia; Ischemic Preconditioning; Ligands; Link; Membrane; Membrane Fluidity; Membrane Microdomains; Mitochondria; Modeling; Molecular; Molecular Biology; Molecular Biology Techniques; Morbidity - disease rate; Mus; Myocardial Ischemia; Myocardium; Patients; Pharmacologic Substance; Phosphotransferases; Physiological; Play; Population; Post-Traumatic Stress Disorders; Receptor Protein-Tyrosine Kinases; Reperfusion Injury; Reperfusion Therapy; Reporting; Research; Risk; Role; Services; Signal Transduction; Signaling Molecule; Stimulus; Techniques; Technology; Testing; Tissues; Veterans; Work; aged; agent orange; base; caveolin-3; clinically relevant; conditioning; insight; male; mortality; new therapeutic target; novel; novel therapeutics; overexpression; pre-clinical; public health relevance; response; statistics

DESCRIPTION (provided by applicant): Myocardial ischemia/reperfusion injury remains a major cause of morbidity and mortality worldwide. The discovery of ischemic preconditioning in the 1980's revealed the presence of a potent endogenous protective mechanism to increase ischemic tolerance in the heart that could be produced by brief periods of ischemia and reperfusion preceding a prolonged ischemia/reperfusion event. Ischemic postconditioning, evoked prior to reperfusion of ischemic tissue, has provided a clinically relevant target for cardiac protection. Numerous endogenous ligands and pharmaceuticals, includeing volatile anesthetics, produce pre and post conditioning in the heart, providing cardiac protection from myocardial ischemia/reperfusion injury. Despite significant insights gained over the last 30 years into mechanisms of cardiac protection, the full potential of harnessing pre and post conditioning in the clinical setting remains unfulfilled. Cardiac protection strategies in the clinical setting are limited by several factors including age and diseases related to aging. We have shown previously that the signaling molecules involved in cardioprotection need to function within caveolae and interact with caveolins to produce effective cardioprotection. We propose to test the novel hypothesis that loss of caveolin and disruption of precise cardioprotective signaling within caveolar microdomains results in the impaired volatile anesthetic-induced cardiac protection evident in aged animals and that re- expression of caveolin can restore volatile anesthetic-induced cardiac protective signaling that has been impaired by aging. The aims of the grant will 1: Determine mechanisms involved the interaction of volatile anesthetics and caveolins at the sarcolemmal membrane in young and aged cardiac myocytes, 2: Determine the mechanisms involved in the interaction of volatile anesthetic-induced cardioprotective signaling molecules, caveolins and mitochondria in young and aged cardiac myocytes, and 3: Determine if overexpression of Cav-3 restores volatile anesthetic-induced cardiac protection in aged mice and human hearts. We will use state of the art molecular biology techniques, electron paramagnetic resonance technology, imaging technology, and physiological techniques in cardiac myocytes, human myocardium and clinically relevant models of I/R injury to focus on mechanism and produce important preclinical data to support the use of caveolins as novel therapeutics for aged veteran patients at risk of myocardial ischemia/reperfusion injury.

描述（由申请人提供）： 心肌缺血/再灌注损伤仍然是全球发病率和死亡率的主要原因。在1980年代发现缺血性预处理的发现表明，存在有效的内源性保护机制，可以增加心脏缺血性耐性，这可能是由于缺血的短期和再灌注在长时间缺血/再灌注事件之前产生的。缺血后的缺血后，在缺血组织再灌注之前引起了诱发，为心脏保护提供了临床相关的靶标。许多内源性配体和药物包括挥发性麻醉药物，在心脏中产生前后的调节性，可通过心肌缺血/再灌注损伤提供心脏保护。尽管在过去30年中获得了心脏保护机制的重大见解，但在临床环境中利用前后条件的全部潜力仍未实现。临床环境中的心脏保护策略受到多种因素的限制，包括年龄和与衰老有关的疾病。我们先前已经表明，与心脏保护作用的信号分子需要在小窝中发挥作用并与小窝蛋白相互作用以产生有效的心脏保护作用。我们建议检验一个新的假设，即caveolar微域内的小窝蛋白的丧失和精确心脏保护信号的破坏会导致挥发性麻醉诱导的心脏保护受损，而在老年动物中可见的心脏保护性，而caveolin的表达可以通过挥发性麻醉诱导的挥发性麻醉剂诱导的信号来恢复敏捷的信号。赠款的目的1：确定机制涉及的机制涉及挥发性麻醉和小窝蛋白在年轻和衰老的心肌细胞中的肌膜膜上的相互作用，2：确定挥发性麻醉诱导的心脏保护信号分子和3个型号ificy and Mimycytria和mi iCochondria及其型号的挥发性麻醉相互作用所涉及的机制CAV-3的过表达恢复了老年小鼠和人类心脏的挥发性麻醉诱导的心脏保护。 We will use state of the art molecular biology techniques, electron paramagnetic resonance technology, imaging technology, and physiological techniques in cardiac myocytes, human myocardium and clinically relevant models of I/R injury to focus on mechanism and produce important preclinical data to support the use of caveolins as novel therapeutics for aged veteran patients at risk of myocardial ischemia/reperfusion injury.