Mitochondrial Quality in Cardioprotection: Overcoming Co-Morbidities

描述（由申请人提供）： 30年的心脏保护研究未能产生有效的治疗干预 在临床环境中，尽管许多药物在动物研究中显示有效。这一失败被广泛归因于这些研究使用了年轻的健康动物，而不是患有急性心肌梗死或心脏手术引起的心肌缺血和再灌注的人类中遇到的共病疾病的动物。高龄、代谢综合征和糖尿病已被证明会干扰心脏保护。此外，炎症在老年人和老年动物中以及在代谢综合征的情况下增加。重要的是，自噬随着年龄或代谢综合征而减少。该提案的中心主题指出，受损的自噬是代谢综合征和衰老的一个特征;受损的自噬有助于炎症，限制心脏保护，并加剧梗死后重塑。受损的自噬阻止了预处理所必需的线粒体自噬，并限制了线粒体的周转，导致低效的、产生ROS的线粒体的积累，这些线粒体激活了炎症信号通路。在三个项目中提出的研究（心肌保护，炎症和线粒体周转）将测试这些相互关联的假设，确定尽管年龄较大或存在代谢综合征，但可以上调自噬的药物，从而恢复心脏保护并改善梗死后结果。除了这些实际的转化目标外，各个项目还包含具体的目标，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和动物生理学，外科和成像核心将支持所有项目，并将推进现有技术。 在五年结束时，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、后处理或药物预处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，以改善不良的梗死后重塑或使成功的心脏保护。 在急性心肌缺血和梗死后重构的背景下，确定自噬/线粒体自噬对炎症的贡献。 识别自噬受损或线粒体周转受损的蛋白质特征，这将预测对心脏保护干预的无反应性。 确定心脏保护状态的蛋白质生物标志物，通过消除受损的线粒体或上调自噬来指示，在猪模型中验证，并研究人类心脏组织。

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.