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Oxidative Stress and Pathological Glutamate Release in Stroke

Award Number: R01NS111943
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Oxidative Stress and Pathological Glutamate Release in Stroke - SUMMARY Stroke is the fifth leading cause of death and the leading cause of adult long-term disability in the U.S. and other industrialized nations. Yet only one therapeutic agent (the clot-dissolving drug tPA) is approved for acute treatment. Among the critical injurious factors in stroke, oxidative stress is thought to contribute to the terminal steps of tissue damage. Antioxidants and free radical scavengers are highly protective in animal stroke models. Yet, for poorly understood reasons, they have shown limited or no benefits in clinical trials. In the prior NIH- sponsored project, we collected strong data which may help to revise our understanding of the mechanisms contributing to oxidative injury in ischemia: (1) In a rat model of stroke, we found that the superoxide dismutase (SOD) mimetic tempol was more protective than clinically used antioxidants. (2) Potent protection by tempol correlated with reduction of redox-sensitive glutamate release in the ischemic penumbra. (3) Glutamate release was mediated by at least two redox-sensitive mechanisms: volume-regulated anion channels (VRAC) and Ca2+- dependent changes in membrane permeability. (4) The glutamate-permeable VRAC was composed of proteins from the leucine-rich repeat-containing family 8 (LRRC8). We have assembled a synergistic team of investi- gators and propose to use highly innovative molecular and animal tools to test the HYPOTHESIS that reactive oxygen species (ROS, particularly superoxide anions) propagate and amplify stroke injury via stimulation of redox-sensitive glutamate release in the clinically relevant penumbra. In the planned studies we will address the following critical questions: (1) Is the LRRC8A-containing VRAC a viable target for neuroprotection in stroke? (2) Is glutamate release via the heteromeric LRRC8 channels responsible for tissue injury? (3) What is the chemical nature of the tempol-targeted ROS and the cellular site of their production? (4) Does glutamate release via VRAC drive disruption at the neurovascular interface (changes in blood flow and BBB integrity)? The immediate goal of the proposed work is to identify new molecular mechanisms that govern oxidative brain injury and determine the protective actions of antioxidants. Our long-term objective is to provide a blueprint for the development of new effective stroke therapies based on SOD mimetics and/or VRAC blockers.


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: 2025 ( Subtotal = -$17 )
2025	2023	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE # A34	ALBANY	NY	12208	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/28/2025	NON-COMPETING CONTINUATION	-$17
														Subtotal = -$17

Issue Date FY: 2023 ( Subtotal = $364,450 )
2023	2023	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/1/2023	NON-COMPETING CONTINUATION	$364,450
														Subtotal = $364,450

Issue Date FY: 2022 ( Subtotal = $364,450 )
2022	2022	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	3/31/2022	NON-COMPETING CONTINUATION	$36,446
2022	2022	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/6/2022	NON-COMPETING CONTINUATION	$328,004
														Subtotal = $364,450

Issue Date FY: 2021 ( Subtotal = $406,530 )
2021	2021	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/27/2021	NON-COMPETING CONTINUATION	$406,530
														Subtotal = $406,530

Issue Date FY: 2020 ( Subtotal = $428,393 )
2020	2020	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/10/2020	NON-COMPETING CONTINUATION	$428,393
														Subtotal = $428,393

Issue Date FY: 2019 ( Subtotal = $461,630 )
2019	2019	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	2/13/2019	NEW	-$24,552
2019	2019	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/23/2019	NEW	$486,182
														Subtotal = $461,630

Grand Total All Awards = $2,025,436

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Oxidative Stress and Pathological Glutamate Release in Stroke

Award Number: R01NS111943

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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