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 关于导致麻醉诱导预适应(ARC)的线粒体功能。我们特别假设 麻醉剂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换(PT)孔的打开，这是一个中心事件 在缺血和再灌流损伤期间。在当前周期中，我们确定了肌膜KATP的作用 作为氧化应激和细胞凋亡的保护者的通道。我们还拿到了关于当地小说的证据 PKC、ROS和NO‘对线粒体KATP通道的调节我们发现分离出的线粒体 在PCK依赖的情况下，接受APC的心脏对钙离子诱导的PT孔道开放更具抵抗力 举止。综上所述，这些数据强烈表明，线粒体功能的调节是 短暂麻醉暴露后的心脏保护。 基于这些非常激动人心的结果和最先进的新型实验的发展 项目II将提供强有力的证据，证明抑制PT孔的打开是最终的 APC实际上影响心脏保护的机制。我们将解决以下具体目标和 假设： 目的1.测定挥发性麻醉药对线粒体生物能谱离子的直接影响 动态平衡和蛋白质组。 目的2.研究麻醉药对甲状旁腺素开放的调节作用。 目的3.确定sarcKATp通道在麻醉诱导线粒体中的作用 保护。 目的4.应用计算模型量化和预测麻醉药对线粒体的影响 生物能量学和功能。 综上所述，线粒体不仅是下游的靶点，也是上游的启动者。 APC。这些研究将为APC信号通路的研究提供新的机制信息。 线粒体水平，这将导致治疗缺血再灌注损伤的新的治疗方法。 我们将研究全身麻醉剂是如何保护心脏免受 线粒体与其胞浆被膜相互作用所致的缺血/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。