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

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世界发病和死亡的主要原因。 20世纪80年代缺血预处理的发现揭示了存在一种有效的内源性保护机制，可以增加心脏的缺血耐受性，这种机制可以通过在长时间的缺血/再灌注事件之前短暂的缺血和再灌注来产生。在缺血组织再灌注之前引发的缺血后处理为心脏保护提供了临床相关目标。许多内源性配体和药物，包括挥发性麻醉剂，在心脏中产生预处理和后处理，提供心脏保护免受心肌缺血/再灌注损伤。尽管过去 30 年人们对心脏保护机制有了深刻的认识，但在临床环境中利用预处理和后处理的全部潜力仍未得到充分发挥。临床环境中的心脏保护策略受到多种因素的限制，包括年龄和与衰老相关的疾病。我们之前已经证明，参与心脏保护的信号分子需要在小窝内发挥作用并与小窝相互作用才能产生有效的心脏保护作用。我们建议测试新的假设，即小窝蛋白的丢失和小窝微域内精确心脏保护信号的破坏导致老年动物中明显的挥发性麻醉剂诱导的心脏保护受损，并且小窝蛋白的重新表达可以恢复因衰老而受损的挥发性麻醉剂诱导的心脏保护信号。该拨款的目的是 1：确定年轻和老年心肌细胞中挥发性麻醉剂与肌膜膜小窝蛋白相互作用的机制，2：确定年轻和老年心肌细胞中挥发性麻醉剂诱导的心脏保护信号分子、小窝蛋白和线粒体相互作用的机制，以及 3：确定是否 Cav-3 的过度表达可恢复老年小鼠和人类心脏中挥发性麻醉剂诱导的心脏保护作用。我们将在心肌细胞、人类心肌和I/R损伤的临床相关模型中使用最先进的分子生物学技术、电子顺磁共振技术、成像技术和生理技术，重点研究机制并产生重要的临床前数据，以支持使用caveolins作为有心肌缺血/再灌注损伤风险的老年退伍军人的新疗法。