Protection of Ischemic Myocardium

保护缺血心肌

• 批准号: 6854919
• 负责人: Roberto Bolli
• 金额: $ 224.62万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-15 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6854919
• 关键词: cytoprotection; genetically modified animals; ischemic preconditioning; laboratory mouse; myocardium

DESCRIPTION (provided by applicant): The heart has evolved an adaptive response to stress, termed late preconditioning (PC), that confers powerful and sustained protection against ischemia/reperfusion injury. Previous work by us and others has shown that late PC is mediated by the upregulation of a cluster of stress-responsive proteins, namely, iNOS, HO-1, and ecSOD, which mitigate tissue injury via the combined regulation of the myocardial levels of NO and CO. Our preliminary data indicate that these proteins are organized hierarchically and interact with one another to effect cytoprotection, thereby forming a functional module. The central theme of this Program Project is to elucidate the molecular mechanisms responsible for the powerful cardioprotective effects of the iNOS-HO-1-ecSOD module, and to explore the feasibility of upregulating this module with genetic or pharmacologic approaches in order to achieve chronic prophylactic cardioprotection. The Program will consist of four Projects and four Cores. Project 1 (Bolli) will determine whether gene therapy strategies that increase myocardial NO and CO levels (iNOS, HO-1, or ecSOD gene therapy) result in a chronically-protected phenotype and will elucidate how these three-stress responsive genes interact in modulating NO and CO levels. This Project will test the novel idea that gene therapy can be used to achieve a permanent preconditioned-like state. Project 2 (Prabhu) will determine whether the same three genes (iNOS, HO-1, and ecSOD) mitigate chronic post-infarction myocardial remodeling and the resulting heart failure, and will investigate the mechanisms for these beneficial effects. The same gene therapy strategies tested in Project 1 in the setting of acute ischemia/reperfusion injury will be tested in Project 2 in the setting of post-infarction LV remodeling. This Project will test the novel idea that the iNOS-HO-1-ecSOD module is a critical protective mechanism against heart failure. Project 3 (Xuan) will investigate the signaling and molecular mechanisms Whereby NO and CO induce delayed protection, focusing on the remarkable ability of these molecules to suppress apoptosis. The central hypothesis of this Project is that the NO-CO axis plays a critical role in the cardiac adaptation to stress by virtue of its ability to genetically reprogram the heart in a manner that promotes cell survival. Project 4 (Bhatnagar) will test the hypothesis that in the preconditioned heart iNOS and HO-1 inhibit mitochondrial respiration, which decreases free radical generation, inhibits mitochondrial permeability transition, and prevents cell death. These four projects will be supported by four Cores that will provide services in mouse surgery, cardiac gene-transfer, transgenic and knockout mouse generation, viral vector production, and pathology. This Program Project is the natural evolution of our previous work on late PC - having identified NO and CO as key mediators of this adaptation, we will investigate the mechanism of protection and the therapeutic utility of the NO-CO axis. Because of the ubiquitous role of NO and CO, the results will have broad pathophysiological implications for numerous biological processes in which NO and CO are known to serve and important regulatory function. In addition, the results may provide a framework for translating cardioprotective therapies to the clinical arena.

描述（由申请人提供）： 心脏已经进化出一种对压力的适应性反应，称为晚期预适应（PC），可以提供强大而持续的保护，防止缺血/再灌注损伤。我们和其他人之前的工作表明，晚期 PC 是由一组应激反应蛋白（即 iNOS、HO-1 和 ecSOD）上调介导的，这些蛋白通过联合调节心肌 NO 和 CO 水平来减轻组织损伤。我们的初步数据表明，这些蛋白按层次组织并相互作用，以实现细胞保护，从而形成功能模块。该项目的中心主题是阐明iNOS-HO-1-ecSOD模块强大的心脏保护作用的分子机制，并探索通过遗传或药理学方法上调该模块以实现慢性预防性心脏保护的可行性。该计划将由四个项目和四个核心组成。项目 1 (Bolli) 将确定增加心肌 NO 和 CO 水平的基因治疗策略（iNOS、HO-1 或 ecSOD 基因治疗）是否会导致长期保护表型，并将阐明这三种应激反应基因如何在调节 NO 和 CO 水平中相互作用。该项目将测试基因疗法可用于实现永久的类预处理状态的新想法。项目 2（Prabhu）将确定相同的三个基因（iNOS、HO-1 和 ecSOD）是否可以减轻慢性梗塞后心肌重塑和由此导致的心力衰竭，并将研究这些有益作用的机制。项目 1 在急性缺血/再灌注损伤中测试的相同基因治疗策略将在项目 2 中在梗塞后左室重塑中进行测试。该项目将测试 iNOS-HO-1-ecSOD 模块是预防心力衰竭的关键保护机制这一新想法。项目3（Xuan）将研究NO和CO诱导延迟保护的信号传导和分子机制，重点关注这些分子抑制细胞凋亡的卓越能力。该项目的中心假设是 NO-CO 轴在心脏对压力的适应中发挥着关键作用，因为它能够以促进细胞存活的方式对心脏进行基因重新编程。项目 4 (Bhatnagar) 将测试以下假设：在预处理的心脏中，iNOS 和 HO-1 抑制线粒体呼吸，从而减少自由基的产生、抑制线粒体通透性转变并防止细胞死亡。这四个项目将得到四个核心的支持，这些核心将提供小鼠手术、心脏基因转移、转基因和基因敲除小鼠生成、病毒载体生产和病理学方面的服务。该项目是我们之前关于晚期 PC 工作的自然演变 - 在确定 NO 和 CO 作为这种适应的关键介质后，我们将研究 NO-CO 轴的保护机制和治疗效用。由于 NO 和 CO 的作用无处不在，因此这些结果将对 NO 和 CO 已知发挥重要调节功能的众多生物过程产生广泛的病理生理学影响。此外，研究结果可能为将心脏保护疗法转化为临床领域提供一个框架。