MITOCHONDRIAL FUNCTION IN ANESTHETIC PRECONDITIONING

麻醉预处理中的线粒体功能

• 批准号: 7600720
• 负责人: Zeljko J. Bosnjak
• 金额: $ 47.78万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7600720
• 关键词: Address; Affect; Alkalinization; Anesthetics; Apoptosis; Arts; Attenuated; Bioenergetics; Cardiac; Cations; Cells; Clinical; Complex; Computer Simulation; Data; Development; Electrophysiology (science); Event; Exposure to; Future; General anesthetic drugs; Generations; Heart; Homeostasis; Ions; Isoflurane; Lead; Lipid Bilayers; Mediating; Mitochondria; Mitochondrial Matrix; Modeling; Oxidative Stress; Permeability; Phosphorylation; Probability; Production; Proteins; Proteome; Proteomics; Rattus; Regulation; Reperfusion Injury; Resistance; Respiration; Role; Signal Pathway; Stress; Testing; Therapeutic; Translating; VDAC1 gene; attenuation; base; design; mitochondrial K(ATP) channel; mitochondrial membrane; mitochondrial permeability transition pore; novel; novel therapeutics; preconditioning; prevent; programs; research study; respiratory

The overall objective of this Project is to directly investigate the specific effects of volatile anesthetics on mitochondrial function that lead to anesthetic-induced preconditioning (ARC). We specifically hypothesize that anesthetics induce changes in mitochondrial bioenergetics and ion fluxes which through downstream mechanisms inhibit or delay opening of the mitochondrial permeability transition (PT) pore, a central event during ischemia and reperfusion injury. During the current cycle we identified a role for the sarcolemmal KATP channels as protectors against oxidative stress and apoptosis. We also obtained evidence on the novel local regulation of the mitochondrial KATP channel by PKC, ROS and NO'. We showed that mitochondria isolated from hearts subjected to APC were more resistant to Ca2+-induced PT pore opening in a PCK dependent manner. Together these data strongly suggest that regulation of mitochondria function is central for cardioprotection following transient anesthetic exposure. Based on these very exciting results and the development of novel state-of-the-art experimental approaches, Project II will furnish strong evidence that inhibition of PT pore opening is an ultimate mechanism by which APC actually affects cardioprotection. We will address the following Specific Aims and hypotheses: Aim 1. Determine the direct effects of volatile anesthetics on mitochondrial bioenergetics, ion homeostasis and proteome. Aim 2. Characterize how anesthetics modulate PT pore opening. Aim 3. Determine the contribution of sarcKATp channel to anesthetic-induced mitochondrial protection. Aim 4. Apply computational models to quantify and predict the effects of anesthetics on mitochondrial bioenergetics and function. In summary, the mitochondrion is not only a downstream target, but also an upstream initiator of APC. These studies will provide novel and mechanistic information of APC signaling pathways at the mitochondrial level which should lead to novel therapeutic approaches to treat ischemia reperfusion injury. Lay description: We will examine how general anesthetics protect the heart against ischemia/reperfusion injury by interactions between mitochondria and their cytosolic envelope. These results will furnish valuable information for translating protective therapies to clinical practice.

该项目的总体目标是直接研究挥发性麻醉剂的具体效果 影响导致麻醉诱导预适应（ARC）的线粒体功能。我们具体假设 麻醉剂会引起线粒体生物能和离子通量的变化，这些变化通过下游 机制抑制或延迟线粒体通透性转变 (PT) 孔的打开，这是一个中心事件 缺血和再灌注损伤期间。在当前周期中，我们确定了肌膜 KATP 的作用 通道作为对抗氧化应激和细胞凋亡的保护剂。我们还获得了有关当地小说的证据 PKC、ROS 和 NO' 对线粒体 KATP 通道的调节。我们证明线粒体被分离 在 PCK 依赖性中，来自接受 APC 的心脏对 Ca2+ 诱导的 PT 孔开放具有更强的抵抗力 方式。这些数据共同有力地表明线粒体功能的调节对于 短暂麻醉暴露后的心脏保护。 基于这些非常令人兴奋的结果和新颖的最先进的实验的发展 方法，项目 II 将提供强有力的证据，证明抑制 PT 孔开放是最终的方法 APC 实际影响心脏保护的机制。我们将实现以下具体目标和 假设： 目标 1. 确定挥发性麻醉剂对线粒体生物能、离子的直接影响 稳态和蛋白质组。 目标 2. 描述麻醉剂如何调节 PT 毛孔张开。 目标 3. 确定 sarcKATp 通道对麻醉诱导的线粒体的贡献 保护。 目标 4. 应用计算模型来量化和预测麻醉剂对线粒体的影响 生物能量学和功能。 综上所述，线粒体不仅是下游靶点，也是上游启动子。 装甲运兵车。这些研究将提供 APC 信号通路的新颖和机制信息。 线粒体水平，这应该会导致治疗缺血再灌注损伤的新治疗方法。 简单描述：我们将研究全身麻醉剂如何保护心脏免受 线粒体与其胞质包膜之间的相互作用造成缺血/再灌注损伤。这些结果 将为将保护性疗法转化为临床实践提供有价值的信息。