Anesthetic-Induced Cardiac Preconditioning

麻醉诱导的心脏预处理

• 批准号: 7918909
• 负责人: Zeljko J. Bosnjak
• 金额: $ 178.17万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-05 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7918909
• 关键词: Anesthetic; Induced; Cardiac; Preconditioning

DESCRIPTION (provided by applicant): Similar to the powerful endogenous cardioprotective mechanism of ischemic preconditioning, anesthetic-induced preconditioning (APC) has emerged as an equally effective cardioprotective intervention with better risk-to-benefit ratio for the patient. During the current cycle of the Program Project we have identified key elements and mechanisms involved in APC. Central to cardioprotection is the knowledge we have gained regarding the regulation of mitochondrial function by volatile anesthetics. Given the fundamental role of mitochondria in myocardial energetics and oxidative stress, we believe that they are a promising target for protective strategies such as APC. In contrast, disease states resistant to APC (e.g. diabetes) contain fundamental disturbances of mitochondrial function. The central theme of this Program Project is to elucidate the molecular mechanisms underlying APC. Specifically, we hypothesize that attenuation of permeability transition (PT) pore opening after ischemia and reperfusion is central to many of the phenotypic differences observed after exposure to volatile anesthetics. This Program will consist of three interrelated research projects supported by two Cores. Project I (Warltier) will focus on defining the temporal sequence of activation of key cardioprotective proteins related to the regulation of NO¿ production via HIF1a-VEGF-NO¿ axis by volatile anesthetics. Disruption of these elements and their effect on sarcKATp channel activity, mitochondrial-derived ROS formation, and tissue and cell injury will be determined. Project II (Bosnjak) will elucidate mechanisms involved in volatile anesthetic-dependent modulation of PT pore opening, a critical end effector of APC. It will address several factors that are critical to the role of the PT pore in APC such as mitochondrial bioenergetics and its proteome and the contribution of sarcKATp channels. Computational models of mitochondrial bioenergetics will be used to test specific hypotheses related to the effects of volatile anesthetics. Project III (Kersten) will investigate mechanisms involved in the attenuation of APC in diabetic animals. It will exploit a novel rat model of type 2 diabetes in which we were able to selectively switch the mitochondrial genome to further dissect the role of mitochondria and eNOS-sensitive pathway during impaired APC. All three Projects will be supported by a Biochemical and Molecular Biology Core (Harder) and a Proteomics Core (Olivier). These Cores will provide state-ofthe- art techniques in gene silencing, real time PCR, mitochondrial proteome, cell cultures, mitochondrial function assays, confocal microscopy and pathology. This Program Project represents a comprehensive effort to leverage our existing infrastructure and programmatic experience in physiology, biophysics, genomics, proteomics, and computational biology to advance our understanding of the cellular and subcellular effects of anesthetics in organ protection. Our findings are likely to have a significant impact in the clinical use of volatile anesthetics.

描述（由适用提供）：类似于缺血性预处理，麻醉诱导的预处理（APC）的强大内源性心脏保护机制（APC）已成为一种同样有效的心脏保护干预措施，患者的风险对效率更好。在程序项目的当前周期中，我们确定了APC中涉及的关键要素和机制。心脏保护的核心是我们获得的有关通过挥发性麻醉的线粒体功能调节的知识。鉴于线粒体在心肌能量和氧化应激中的基本作用，我们认为它们是保护诸如APC之类的策略的承诺目标。相比之下，抗APC（例如糖尿病）的疾病状态包含线粒体功能的基本疾病。 该计划项目的中心主题是阐明APC的分子机制。具体而言，我们假设缺血和再灌注后渗透性转变（PT）孔的衰减对于暴露于挥发性麻醉剂后观察到的许多表型差异至关重要。该计划将由两个核心支持的三个相互关联的研究项目组成。项目I（Warltier）将重点放在定义与通过HIF1A-VEGF-NO轴调节NO生产相关的关键心脏保护蛋白激活的临时激活顺序，该蛋白质是通过挥发性麻醉药而进行的。这些元素的破坏及其对sarckatp通道活性，线粒体衍生的ROS的影响以及组织和细胞损伤的影响。项目II（Bosnjak）将阐明参与PT孔口的挥发性麻醉依赖性调制的机制，PT孔口是APC的关键终端效应子。它将解决对PT孔在APC中的作用至关重要的几个因素，例如线粒体生物能及其蛋白质组以及SARCKATP通道的贡献。线粒体生物能学的计算模型将用于测试与挥发性麻醉药有关的特定假设。 III项目（Kersten）将研究糖尿病动物中APC衰减的机制。它将利用一种新型的2型糖尿病大鼠模型，在该模型中，我们能够选择性地切换线粒体基因组，以进一步剖析受损APC期间线粒体和eNOS敏感途径的作用。这三个项目将得到生化和分子生物学核心（硬）和蛋白质组学核心（Olivier）的支持。这些核心将在基因沉默，实时PCR，线粒体蛋白质组，细胞培养物，线粒体功能测定，共聚焦显微镜和病理学方面提供最先进的技术。 该计划项目代表了一项全面的努力，以利用我们在生理学，生物物理学，基因组学，蛋白质组学和计算生物学方面的现有基础设施和程序经验，以促进我们对麻醉器在器官保护中的细胞和亚细胞影响的理解。我们的发现可能会对挥发性麻醉药的临床使用产生重大影响。