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

项目摘要/摘要 我们的首要目标是确定支持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，代表着追求这一目标的下一步 目的是明确挥发性麻醉药对组织特异性和循环的影响和机制。 在挥发性麻醉剂存在已知发病风险的情况下以及在代谢状态下的代谢 酮病。 挥发性麻醉剂在现代医学中是无价的工具。尽管它们被广泛使用，但精确的分子 挥发性麻醉剂(VA)的作用机制在很大程度上仍不清楚。在有数据的地方，一个综合体 画面浮现出来。实验证据表明，多个直接靶点在两种情况下 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体I(ETC CI)。在已知的分子靶标中 关于维生素A，每种物质对维生素A功能效应的相对贡献还知之甚少。虚拟助理通常是 被认为没有长期后遗症，但特定人群的患者有固有的风险 VAS的有害影响。例如，年龄的两个极端都对以下中枢神经系统损害敏感 麻醉剂暴露。此外，患有原发线粒体疾病的患者对VAS过敏； 文献中有许多关于患有线粒体疾病的儿童在例行程序后死亡的报道 麻醉剂。不明原因的VAS极端反应很少见，但在临床上仍是一个令人担忧的问题 练习一下。了解麻醉不良反应的潜在机制可能会带来改善 患者筛查、监测和护理。高危人群可能会从这一知识中受益最多，但鉴于 所有VA都有可能影响患者预后的非目标效应，了解其机制可能 在整个领域带来更安全的做法。 本提案的目标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情况下的循环代谢，以及潜在的 干预改变新陈代谢的治疗益处。我们假设新陈代谢的改变 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。明确VA暴露对新陈代谢的作用将为了解这些复杂的情况提供新的见解 毒品。

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.