The role of ketone metabolism in sequelae resulting from volatile anesthetic exposure.

酮代谢在挥发性麻醉剂暴露引起的后遗症中的作用。

• 批准号: 10425335
• 负责人: Simon C Johnson
• 金额: $ 37.2万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10425335
• 关键词: Acute; Age; Anesthesia procedures; Anesthetics; Attenuated; Blood; Brain; Caring; Cessation of life; Child; Chronic; Citric Acid Cycle; Complex; Consumption; Data; Defect; Dose; Electron Transport; Exposure to; FRAP1 gene; Fasting; General anesthetic drugs; Genetic Models; Glucose; Goals; Halothane; Hypersensitivity; Iatrogenesis; Ion Channel; Isoflurane; Ketones; Ketosis; Knockout Mice; Knowledge; Lead; Lipids; Literature; Liver; Mediating; Metabolic; Metabolism; Mitochondria; Mitochondrial Diseases; Modern Medicine; Molecular; Molecular Target; Monitor; Morbidity - disease rate; Mus; Neurocognitive Deficit; Pathologic; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Physiological; Population; Populations at Risk; Reporting; Risk; Role; Sensory Receptors; Source; Supplementation; Testing; Therapeutic; Tissues; Toxic effect; aged; clinical practice; detection of nutrient; improved; insight; ketogenesis; liver metabolism; long-term sequelae; mitochondrial dysfunction; mortality; neonatal mice; neonate; neurotoxicity; novel; patient population; patient screening; preference; programs; response; sedative; sevoflurane; tool

Project Summary/Abstract Our overarching goal is to define the molecular mechanisms underpinning the actions of VA compounds. Our overall objective in the studies proposed here, which represent the next step in pursuing this goal, is to define the impact and mechanisms of volatile anesthetics on tissue-specific and circulating metabolism in conditions where volatile anesthetics carry known risks of morbidity and in states of metabolic ketosis. Volatile anesthetics are invaluable tools in modern medicine. Despite their prevalent use, the precise molecular mechanisms of volatile anesthetic (VA) activity remain largely unclear. Where data are available, a complex picture emerges. Experimental evidence has revealed multiple direct targets mediating both the anesthetic/sedative and non-anesthesia related effects of these agents, including neuro-receptors, ion channels, and mitochondrial electron transport chain complex I (ETC CI). Among known molecular targets of VA’s, the relative contributions of each to the functional effects of VAs is poorly understood. VAs are generally regarded as devoid of long term sequelae, but specific populations of patients are at risk for intrinsic detrimental effects of VAs. For example, both extremes of age are sensitive to CNS damage following anesthetic exposure. Additionally, patients with primary mitochondrial disorders are hypersensitive to VAs; the literature harbors multiple reports of children with mitochondrial disease who have died after a routine anesthetic. Unexplained extreme responses to VAs are rare, but also remain a source of concern in clinical practice. Understanding the mechanisms underlying negative responses to anesthesia may lead to improved patient screening, monitoring, and care. At-risk populations may benefit most from this knowledge, but, given that all VAs have off target effects that may impact patient outcomes, understanding their mechanisms may lead to safer practices throughout the field. The goal of this proposal is to define impact and mechanisms of volatile anesthetics on tissue-specific and circulating metabolism in conditions where volatile anesthetics carry known risks of morbidity, and the potential therapeutic benefit of intervening in altered metabolism. We hypothesize that altered metabolism mediates multiple sequelae of VA exposure in sensitive populations, including both toxicity and neurocognitive deficits in sensitive settings. Defining the role of VA exposure on metabolism will provide new insights into these complex drugs.

项目摘要/摘要 我们的总体目标是定义支持VA作用的分子机制 化合物。我们在这里提出的研究中的总体目标，这代表了追求这一目标的下一步 目标是定义挥发性麻醉药对组织特异性和循环的影响和机制 在挥发性麻醉剂具有已知发病风险和代谢状态的疾病中的新陈代谢 酮症。 挥发性麻醉是现代医学中的宝贵工具。尽管它们普遍存在，但精确的分子 挥发性麻醉（VA）活性的机制在很大程度上尚不清楚。在可用数据的地方，一个复杂的 图片出现。实验证据揭示了介导的多个直接目标 这些药物的麻醉/镇静和非麻醉相关效应，包括神经受体，离子 通道和线粒体电子传输链复合物I（ETC CI）。在已知的分子靶标 VA的，每个人对VA的功能效应的相对贡献知之甚少。 VA通常是 被认为没有长期后遗症，但特定的患者种群有内在的风险 VAS的不利影响。例如，两个极端的年龄均对CNS伤害敏感 麻醉暴露。另外，原发性线粒体疾病患者对VAS过敏。这 文学藏有多个关于线粒体疾病儿童的报告 麻药。对VA的无法解释的极端反应很少 实践。了解对麻醉的负面反应的基础机制可能会改善 患者筛查，监测和护理。处于危险的人口可能会从这些知识中受益最大，但是，给予 所有VA都具有可能影响患者结果的目标影响，了解其机制可能 导致整个领域的安全实践。 该提案的目的是确定挥发性麻醉剂对组织特异性和的影响和机制 在挥发性麻醉剂具有已知风险和潜力的情况下，循环代谢循环代谢 干预改变新陈代谢的治疗益处。我们假设改变了新陈代谢媒体 敏感人群中VA暴露的多次后遗症，包括毒性和神经认知缺陷 敏感设置。定义VA暴露对新陈代谢的作用将为这些复杂的新见解 毒品。