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: 9797098
• 负责人: Margaret Mary Sedensky
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9797098
• 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; Neonatal; 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; mitochondrial dysfunction; mortality; 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.

项目概要/摘要 我们的首要目标是确定 VA 作用的分子机制 我们在此提出的研究的总体目标，代表了追求这一目标的下一步。 目标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和代谢状态下的新陈代谢 酮症。 挥发性麻醉剂在现代医学中是非常宝贵的工具，尽管它们被广泛使用，但精确的分子麻醉剂。 挥发性麻醉剂（VA）活性的机制在很大程度上仍不清楚，但有数据可查，这是一个复杂的过程。 实验证据显示，有多个直接目标介导这两种情况。 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) 的已知分子靶点。 人们普遍对 VA 的功能作用的相对贡献知之甚少。 被认为没有长期后遗症，但特定人群的患者存在内在风险 例如，两种极端年龄都对中枢神经系统损伤敏感。 此外，患有原发性线粒体疾病的患者对 VA 过敏； 文献中有多篇关于患有线粒体疾病的儿童在例行公事后死亡的报道 对 VA 的不明原因的极端反应很少见，但仍然是临床关注的一个问题。 了解麻醉不良反应的机制可能会导致改善。 患者筛查、监测和护理可能会从这些知识中受益最多，但考虑到这一点。 所有 VA 都有可能影响患者治疗结果的脱靶效应，了解其机制可能会 导致整个领域更安全的实践。 该提案的目标是定义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情况下的循环代谢，以及潜在的风险 干预改变治疗代谢的好处。 敏感人群暴露于 VA 会产生多种后遗症，包括毒性和神经认知缺陷 定义 VA 暴露对新陈代谢的作用将为这些复杂的环境提供新的见解。 药物。