Mitochondrial Quality in Cardioprotection: Overcoming Co-Morbidities

心脏保护中的线粒体质量：克服并发症

基本信息

批准号：
8683224
负责人：
Roberta A. Gottlieb
金额：
$ 240.98万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (Provided by applicant): Thirty years of cardioprotection research have failed to yield a therapeutic intervention effective in the clinical setting, despite numerous agents shown to be effective in animal studies. This failure is widely attributed to the use of young healthy animals for these studies, rather than animals with the comorbid conditions encountered in humans suffering from myocardial ischemia and reperfusion arising from acute myocardial infarction or cardiac surgery. Advanced age, metabolic syndrome, and diabetes have been shown to interfere with cardioprotection. Moreover, inflammation is increased in the elderly and in aged animals, as well as in the setting of metabolic syndrome. Importantly, autophagy is diminished with age or metabolic syndrome. The central theme of this proposal states that impaired autophagy is a feature of metabolic syndrome and aging; impaired autophagy contributes to inflammation, limits cardioprotection, and exacerbates postinfarction remodeling. Impaired autophagy prevents mitophagy essential for preconditioning, and limits mitochondrial turnover, resulting in the accumulation of inefficien, ROS-producing mitochondria that activate inflammatory signaling pathways. The studies proposed in the three Projects (Cardioprotection, Inflammation, and Mitochondrial Turnover) will test these interconnected hypotheses, identify agents that can upregulate autophagy despite advanced age or the presence of metabolic syndrome, and thereby restore cardioprotection and improve postinfarction outcomes. In addition to these practical translational objectives, the individual projects contain specific aims which will provide detailed molecular insights into process of cardioprotection, as well as the alterations arising as a result of aging or metabolic syndrome (MetS). The technology-driven Proteomics Core and the Animal Physiology, Surgery, and Imaging Core will support all projects and will also advance existing technology. At the end of five years, our common goals are to: Establish the impact of age, diet-induced obesity, and MetS on autophagy and the ability to achieve cardioprotection through ischemic preconditioning, postconditioning, or pharmacologic conditioning Determine whether an autophagy-inducing drug can mitigate the effects of age or metabolic syndrome to ameliorate adverse postinfarction remodeling or to enable successful cardioprotection. Establish the contribution of autophagy/mitophagy to inflammation in the context of acute myocardial ischemia and postinfarction remodeling. Identify protein signatures of impaired autophagy or impaired mitochondrial turnover, which would predict unresponsiveness to cardioprotective interventions. Identify protein biomarkers for the cardioprotected state, indicated by elimination of damaged mitochondria or up-regulated autophagy, validate in swine models, and study human heart tissue.

描述（由申请人提供）：三十年的心脏保护研究未能产生有效的治疗干预措施在临床环境中，尽管许多药物在动物研究中被证明是有效的。这一失败被广泛归因于这些研究中使用了年轻的健康动物，而不是患有人类因急性心肌梗塞或心脏手术引起的心肌缺血和再灌注而遇到的共病的动物。高龄、代谢综合征和糖尿病已被证明会干扰心脏保护。此外，老年人和老年动物以及代谢综合征的情况下炎症会增加。重要的是，自噬会随着年龄或代谢综合征而减弱。该提案的中心主题指出，自噬受损是代谢综合征和衰老的一个特征；自噬受损会导致炎症，限制心脏保护作用，并加剧梗塞后重塑。自噬受损会阻止预处理所必需的线粒体自噬，并限制线粒体周转，导致产生活性氧的线粒体效率低下，从而激活炎症信号通路。三个项目（心脏保护、炎症和线粒体周转）中提出的研究将测试这些相互关联的假设，找出在高龄或存在代谢综合征的情况下仍能上调自噬的药物，从而恢复心脏保护并改善梗死后的结果。除了这些实用的转化目标之外，各个项目还包含具体目标，这些目标将为心脏保护过程以及衰老或代谢综合征（MetS）引起的变化提供详细的分子见解。技术驱动的蛋白质组学核心以及动物生理学、外科和成像核心将支持所有项目，并将推进现有技术。五年结束时，我们的共同目标是：确定年龄、饮食诱导的肥胖和 MetS 对自噬的影响以及通过缺血预处理、后处理或药物调理实现心脏保护的能力确定自噬诱导药物是否可以减轻年龄或代谢综合征的影响，从而改善梗塞后不良重塑或实现成功的心脏保护。确定自噬/线粒体自噬在急性心肌缺血和梗塞后重塑背景下对炎症的贡献。识别自噬受损或线粒体周转受损的蛋白质特征，这可以预测对心脏保护干预措施的无反应。识别心脏保护状态的蛋白质生物标志物，通过消除受损线粒体或上调自噬来指示，在猪模型中进行验证，并研究人类心脏组织。