Ischemic Injury and Protection

描述（由申请人提供）： 在过去的二十年里，对缺血性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学过程的细胞事件的理解。然而，关于心脏细胞死亡和存活的特定分子和信号机制存在重大争议。我们认为，在缺乏相关分子及其各自的相互作用在亚蛋白质组水平的彻底调查的情况下，使用不同的模型隔离和分析个别蛋白质，阻碍了蛋白质如何有助于在体内表型的准确表征。这些问题反过来又对过去20年基础科学进步转化为改善缺血性心脏病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和机制进步提供了巨大的机会。我们认为，一个显着的范式转变，需要加速心肌缺血领域的转化研究。因此，我们独特的研究团队不依赖于一个特定的实验模型，而是使用系统，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型蛋白质组学技术平台能够系统地检查蛋白质及其相关伙伴，而不是将研究集中在一个途径和/或单个分子上，即，在缺血性损伤和心脏保护中起作用的亚蛋白质组。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目标验证过程。该验证过程将通过各个项目中组装的最先进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，这在组合将允许全面和明确的调查缺血性损伤和保护的机制性质。重要的是，这些研究将靶向参与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起其细胞效应的离散分子背景。这些研究将阐明更准确的治疗干预靶点，因此本质上更适用于临床前竞技场。

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.