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The role of astrocytes in emergence from volatile anesthetics

Award Number: R01GM144368
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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The role of astrocytes in emergence from volatile anesthetics - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2025	UNIVERSITY OF NORTHUMBRIA AT NEWCASTLE	SUTHERLAND BUILDING	NEWCASTLE UPON TYNE				GBR	Biomedical Research and Research Training	000	4	1/16/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $230,364 )
2025	2025	UNIVERSITY OF NORTHUMBRIA AT NEWCASTLE	SUTHERLAND BUILDING	NEWCASTLE UPON TYNE				GBR	Biomedical Research and Research Training	000	4	4/11/2025	NON-COMPETING CONTINUATION	$230,364
														Subtotal = $230,364

Issue Date FY: 2024 ( Subtotal = $223,645 )
2024	2024	UNIVERSITY OF NORTHUMBRIA AT NEWCASTLE	SUTHERLAND BUILDING	NEWCASTLE UPON TYNE				GBR	Biomedical Research and Research Training	000	3	1/29/2024	NON-COMPETING CONTINUATION	$201,281
2024	2024	UNIVERSITY OF NORTHUMBRIA AT NEWCASTLE	SUTHERLAND BUILDING	NEWCASTLE UPON TYNE				GBR	Biomedical Research and Research Training	001	3	6/12/2024	NON-COMPETING CONTINUATION	$22,364
2024	2023	UNIVERSITY OF NORTHUMBRIA AT NEWCASTLE	SUTHERLAND BUILDING	NEWCASTLE UPON TYNE				GBR	Biomedical Research and Research Training	003	2	8/20/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$74,355
2024	2022	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Biomedical Research and Research Training	002	1	8/20/2024	NEW	-$74,355
														Subtotal = $223,645

Issue Date FY: 2023 ( Subtotal = $228,806 )
2023	2023	UNIVERSITY OF NORTHUMBRIA AT NEWCASTLE	SUTHERLAND BUILDING	NEWCASTLE UPON TYNE				GBR	Biomedical Research and Research Training	001	2	4/21/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$228,806
2023	2022	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Biomedical Research and Research Training	000	1	4/21/2023	NEW	$0
														Subtotal = $228,806

Issue Date FY: 2022 ( Subtotal = $423,335 )
2022	2022	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Biomedical Research and Research Training	000	1	2/25/2022	NEW	$423,335
														Subtotal = $423,335

Grand Total All Awards = $1,106,150

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The role of astrocytes in emergence from volatile anesthetics

Award Number: R01GM144368

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/01/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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