Ischemic Injury and Protection

描述(由申请人提供)： 在过去的二十年里，对缺血损伤和心脏保护的研究极大地促进了我们对介导这些生物过程的细胞事件的理解。然而，关于心肌细胞死亡和存活的特定分子和信号机制仍存在重大争议。我们认为，在缺乏对相关分子及其在亚蛋白质组水平上各自相互作用的彻底研究的情况下，在分离和分析单个蛋白质时使用发散模型，阻碍了对蛋白质如何在体内贡献表型的准确表征。这些问题反过来又对过去20年的基础科学进步转化为改善缺血性心脏病的治疗产生了负面影响。 该计划项目采用了一种新的方法来解决上述限制，因此为心肌缺血和心脏保护领域的概念性和机械性进步提供了巨大的机会。我们认为，需要一个重大的范式转变，以加快心肌缺血领域的翻译研究。因此，我们独特的研究团队不再依赖于一个特定的实验模型，而是能够使用系统、器官、细胞和细胞器水平的一系列模型来表征特定蛋白质的作用。蛋白质组学核心提供的新的蛋白质组学技术平台不是将研究集中在一个单独的途径和/或单个分子上，而是使系统地研究蛋白质及其相关伙伴，即蛋白质在缺血损伤和心脏保护中发挥作用的亚蛋白质组。此外，在亚蛋白质组图谱研究之后，我们的研究团队将进行严格的靶标验证过程。这一验证过程将由在单个项目中组装的最先进的技术以及心脏生物学核心来促进。这些技术包括心脏靶向诱导转基因、高分辨率共聚焦显微镜和综合生理学，这些技术结合在一起将允许全面和明确地研究缺血损伤和保护的机制性质。重要的是，这些研究将针对涉及生理表型的亚蛋白质组，因此，这些发现将有助于理解特定分子引发其细胞效应的离散分子背景。这些研究将阐明治疗干预的更准确的靶点，因此将本质上更容易翻译到临床前领域。

DESCRIPTION (provided by applicant): Investigations of ischemic injury and cardiac protection over the past two decades have greatly advanced our understanding of the cellular events that mediate these biological processes. However, significant controversies exist with regard to the specific molecules and signaling mechanisms that underlie cardiac cell death and survival. We believe that the use of divergent models in isolation and the analysis of individual proteins-in the absence of thorough investigation of the associated molecules and their respective interactions at the subproteomic level-has hampered accurate characterization of how proteins contribute to a phenotype in vivo. These issues have in turn negatively impacted the translation of basic science advances of the past 20 years to improved treatment of ischemic heart disease. This Program Project takes a novel approach to address the aforementioned limitations and therefore affords great opportunities for conceptual and mechanistic advancement of the field of myocardial ischemia and cardiac protection. We feel that a significant paradigm shift is required to accelerate translational research in the area of myocardial ischemia. Accordingly, instead of relying on one particular experimental model, our unique team of investigators enables the characterization of the role of specific proteins using an array of models at the system, organ, cell and organelle levels. Instead of focusing the study on one pathway and/or a single molecule in isolation, the novel proteomic technology platform provided by the Proteomic Core enables systematic examination of a protein and its associating partners, i.e., the subproteome in which the protein functions in the setting of ischemic injury and cardiac protection. Moreover, subsequent to subproteome mapping studies, our investigator team will engage in a rigorous target validation process. This validation process will be facilitated by the state-of-the-art techniques assembled in individual Projects as well as the Heart Biology Core. These techniques include cardiac-targeted inducible transgenesis, high resolution confocal microscopy, and integrative physiology, which in combination will allow for comprehensive and unequivocal investigation of the mechanistic nature of ischemic injury and protection. Importantly, these studies will target subproteomes involved in physiologic phenotypes and therefore the findings will facilitate an understanding of the discrete molecular context in which specific molecules elicit their cellular effects. These investigations will elucidate more accurate targets for therapeutic intervention and thus will be inherently more translatable to the pre-clinical arena.