The role of astrocytes in emergence from volatile anesthetics
星形胶质细胞在挥发性麻醉剂苏醒中的作用
基本信息
- 批准号:10340339
- 负责人:
- 金额:$ 42.33万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-01 至 2023-02-28
- 项目状态:已结题
- 来源:
- 关键词:AddressAgitationAnesthesia proceduresAnestheticsAnimalsAnxietyArousalAstrocytesBrainBrain regionCalcium SignalingCell CommunicationCell Culture TechniquesCell modelCellsComplexConfusionConsciousDangerousnessDataDeliriumDevelopmentDoseElderlyElectron TransportEnterobacteria phage P1 Cre recombinaseExcisionExposure toFunctional disorderGeneral AnesthesiaGlutamatesGoalsHypersensitivityImpairmentIn VitroInjuryInterventionKnockout MiceKnowledgeLinkLocationLoxP-flanked alleleMaintenanceMammalsMediatingMedical Care CostsMetabolicMetabolismMicroinjectionsMitochondriaModelingMolecularMusNeuraxisNeuronsNeurotransmittersNorepinephrineOperating RoomsPatientsPharmacologyPlayPopulationPrevalenceProcessProteinsRecoveryRecyclingReportingResearchRiskRoleSynapsesViralVulnerable PopulationsWakefulnessWorkbasecell typeexperimental studyin vivoinsightmitochondrial dysfunctionmitochondrial metabolismmouse modelneural circuitnovelpediatric patientspleiotropismpromoterrelating to nervous systemresponse
项目摘要
Project Summary
Our overarching goal is to define the molecular and cellular mechanisms underlying the actions of
volatile anesthetics (VAs). Our objective in the studies proposed here, which represent the next step in
pursuing this goal, is to mechanistically define the functions of astrocytes that underly their involvement in the
process of emergence from anesthesia with VAs. We hypothesize, based on substantial recent and preliminary
data, astrocyte mitochondrial electron transport chain (ETC) function supports normal emergence through
maintenance of astrocyte calcium signaling, gliotransmitter release, and metabolic support to neurons. We
further hypothesize that specific, spatially defined, populations of astrocytes within the central nervous system
(CNS) drive emergence through their local support of neuronal synapses involved in emergence.
Our experiments will take advantage of pure primary astrocyte cell culture, a mouse model for cell-specific
disruption of mitochondrial function through cre-mediated excision of the ETC complex I protein Ndufs4, and
stereotactic microinjection targeted viral delivery of an astrocyte promoter driven cre-recombinase to enable
brain region-specific disruption of Ndufs4 specifically in astrocytes. These models will allow us to characterize
the astrocyte functions impacted by VAs and the population of astrocytes involved in emergence. Specifically,
they will allow us to: i) define the effects of VAs on astrocyte calcium signaling and mitochondrial function, and
the mechanistic links between the two, in vitro; ii) characterize the effects of VAs on astrocyte gliotransmitter
release; iii) characterize the impact of VAs on astrocyte metabolites which support neuronal function; iv) define
the astrocyte population, defined by region, responsible for supporting emergence from anesthesia with VAs.
Ultimately, this work will greatly advance our understanding of the mechanisms of VA activity and the process of
emergence.
Relevance
Despite their prevalence, the precise targets of VAs, and the mechanisms underlying their pleiotropic effects,
are largely undefined. Emergence is a daily occurrence for thousands of patients, but the process of emergence
is poorly understood. Delays in emergence are associated with anxiety, confusion, resistive activity, delays in
the operating room, increased risks of injury, and significant medical costs. If the mechanisms of emergence can
be resolved, it may be possible to develop strategies for active promotion of recovery of consciousness.
项目概要
我们的首要目标是定义潜在的分子和细胞机制
挥发性麻醉剂(VA)。我们在此提出的研究目标代表了下一步
为了实现这一目标,我们需要机械地定义星形胶质细胞的功能,这些功能是其参与
VA 麻醉苏醒的过程。我们假设,基于最近的大量和初步的
数据显示,星形胶质细胞线粒体电子传递链(ETC)功能通过以下方式支持正常出现:
维持星形胶质细胞钙信号传导、神经胶质递质释放以及对神经元的代谢支持。我们
进一步假设中枢神经系统内特定的、空间定义的星形胶质细胞群
(中枢神经系统)通过对参与涌现的神经元突触的局部支持来驱动涌现。
我们的实验将利用纯原代星形胶质细胞培养物,这是一种用于细胞特异性的小鼠模型
通过 cre 介导的 ETC 复合物 I 蛋白 Ndufs4 的切除破坏线粒体功能,以及
立体定向显微注射靶向病毒递送星形胶质细胞启动子驱动的 cre 重组酶,以实现
Ndufs4 的大脑区域特异性破坏,特别是在星形胶质细胞中。这些模型将使我们能够描述
受 VA 影响的星形胶质细胞功能以及参与出现的星形胶质细胞群。具体来说,
它们将使我们能够:i) 定义 VA 对星形胶质细胞钙信号传导和线粒体功能的影响,以及
两者之间的体外机械联系; ii) 表征 VA 对星形胶质细胞胶质递质的影响
发布; iii) 表征 VA 对支持神经元功能的星形胶质细胞代谢物的影响; iv) 定义
按区域定义的星形胶质细胞群,负责支持从 VA 麻醉中苏醒。
最终,这项工作将极大地增进我们对 VA 活性机制和过程的理解。
的出现。
关联
尽管VAs很普遍,但VAs的精确目标及其多效性作用的机制,
很大程度上是未定义的。苏醒对于成千上万的患者来说是家常便饭,但苏醒的过程
人们对此知之甚少。苏醒延迟与焦虑、混乱、抵抗活动、反应迟缓有关。
手术室、受伤风险增加以及巨额医疗费用。如果涌现机制能够
如果解决了,就有可能制定积极促进意识恢复的策略。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Simon C Johnson其他文献
Evaluating the efficacy of vatiquinone in preclinical models of mitochondrial disease
评估万替醌在线粒体疾病临床前模型中的功效
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
Ernst;Yihan Chen;Michael Mulholland;Vivian Truong;K. James;Allison Hanaford;Simon C Johnson - 通讯作者:
Simon C Johnson
Simon C Johnson的其他文献
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{{ truncateString('Simon C Johnson', 18)}}的其他基金
The role of astrocytes in emergence from volatile anesthetics
星形胶质细胞在挥发性麻醉剂苏醒中的作用
- 批准号:
10776191 - 财政年份:2022
- 资助金额:
$ 42.33万 - 项目类别:
Developmental mechanisms of CNS pathology in mitochondrial disease
线粒体疾病中枢神经系统病理学的发育机制
- 批准号:
10296147 - 财政年份:2021
- 资助金额:
$ 42.33万 - 项目类别:
Developmental mechanisms of CNS pathology in mitochondrial disease
线粒体疾病中枢神经系统病理学的发育机制
- 批准号:
10468301 - 财政年份:2021
- 资助金额:
$ 42.33万 - 项目类别:
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。
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10425335 - 财政年份:2019
- 资助金额:
$ 42.33万 - 项目类别:
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:
10187595 - 财政年份:2019
- 资助金额:
$ 42.33万 - 项目类别:
The role of mTOR in mitochondrial encephalopathy
mTOR 在线粒体脑病中的作用
- 批准号:
9920237 - 财政年份:2017
- 资助金额:
$ 42.33万 - 项目类别:
Functional Characterization and Physiological Consequences of Human Longevity-Associated IGF1R Variants
人类长寿相关 IGF1R 变异体的功能特征和生理后果
- 批准号:
9136482 - 财政年份:2015
- 资助金额:
$ 42.33万 - 项目类别:
Functional Characterization and Physiological Consequences of Human Longevity-Associated IGF1R Variants
人类长寿相关 IGF1R 变异体的功能特征和生理后果
- 批准号:
9062284 - 财政年份:2015
- 资助金额:
$ 42.33万 - 项目类别:
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