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.

项目总结/摘要 我们的首要目标是确定VA作用的分子机制 化合物.我们在这里提出的研究的总体目标，这代表了追求这一目标的下一步 目的是确定挥发性麻醉剂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的条件下以及在代谢性麻醉剂的代谢状态下， 酮症 挥发性麻醉剂是现代医学中无价的工具。尽管它们被广泛使用， 挥发性麻醉剂（VA）活性的机制在很大程度上仍不清楚。如果有数据， 画面浮现。实验证据表明，多个直接靶点介导了 这些药物的麻醉/镇静和非麻醉相关作用，包括神经受体、离子 通道和线粒体电子传递链复合物I（ETC CI）。在已知的分子靶点中， VA的，每个VA的功能效果的相对贡献知之甚少。一般来说， 被认为没有长期后遗症，但特定人群的患者有内在的风险 有害的影响。例如，两个年龄的极端都对以下CNS损伤敏感： 麻醉剂暴露此外，患有原发性线粒体疾病的患者对VA过敏; 文献中有多份报告称，患有线粒体疾病的儿童在常规治疗后死亡， 麻醉剂对VA的不明原因的极端反应是罕见的，但在临床上仍然是一个值得关注的问题。 实践了解对麻醉的负反应的潜在机制可能会改善 患者筛查、监测和护理。高危人群可能从这一知识中受益最多，但鉴于 所有VA都有可能影响患者结局的脱靶效应，了解其机制可以 在整个领域采取更安全的做法。 本提案的目的是确定挥发性麻醉剂对组织特异性和 在挥发性麻醉剂具有已知发病风险的条件下的循环代谢，以及 干预代谢改变的治疗益处。我们假设代谢的改变介导了 敏感人群中VA暴露的多种后遗症，包括毒性和神经认知缺陷， 敏感设置。定义VA暴露对代谢的作用将为这些复杂的疾病提供新的见解。 毒品