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AQP4 and glymphatic function in post-stroke recovery

Award Number: R01NS124206
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: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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AQP4 and glymphatic function in post-stroke recovery - SUMMARY Stroke is a leading cause of death and long-term disability. Brain edema is the most common life- threatening complication following an acute stroke event. It leads to elevated intracranial pressure that will affect the spared areas surrounding the stroked tissue. The preservation of such areas is critical in reducing brain injury and promoting long-term recovery. Understanding the pathophysiology of brain edema is key to identifying therapeutic targets and reducing the final disability burden related to acute stroke. The glymphatic system is a recently discovered waste clearance pathway in the brain. It removes interstitial metabolic waste products, as well as excessive interstitial fluid (ISF), by facilitating the exchange of ISF and cerebrospinal fluid (CSF). With drastically increased metabolic byproducts and the development of cerebral edema, the glymphatic system may play a critical role in post-stroke recovery. Further, aquaporin-4 (AQP4), a water channel protein that has been recognized to be involved in cerebral edema, also drives the glymphatic system. However, due to the limited means of evaluating the glymphatic function in vivo, our current understanding of the role of AQP4 and the glymphatic system in post-stroke recovery is still quite limited. The goal of this project is to develop novel MRI methods for quantitative assessment of the glymphatic function in vivo and to apply these methods to investigate the role of AQP4 and the glymphatic system in post-stroke edema formation and reabsorption. Specifically, we will develop and validate a 3D magnetic resonance fingerprinting (MRF) method for dynamic and simultaneous tracking of a gadolinium (Gd)-based, large molecular weight (MW) paravascular tracer (GadoSpin, MW=200 kDa, primarily a T1 contrast agent) and oxygen-17 (17O) enriched water (H217O, MW=19 Da, a T2 contrast agent) in mouse brain (Aim 1). This approach will enable the simultaneous evaluation of CSF flow in the paravascular space and CSF-ISF exchange between the paravascular space and brain parenchyma in a single MRF scan. Kinetic analysis methods will be developed for quantitative assessment of the glymphatic function from MRF measurements, including the CSF flow in the paravascular conduits and the CSF-ISF exchange rate and water transport in the glymphatic pathway (Aim 2). These methods will be applied to evaluate the effects of AQP4 knockout and inhibition on edema formation and reabsorption in two mouse models of ischemic (cytotoxic edema) and hemorrhagic (vasogenic edema) stroke (Aim 3). Successful completion of the project will give rise to a novel MRI method for in vivo quantification of glymphatic function. Application of this method to the investigation of post-stroke pathophysiology will lead to new insights into the role of AQP4 and the glymphatic system in post-stroke edema.


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 = $693,242 )
2026	2026	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	4/7/2026	NON-COMPETING CONTINUATION	$693,242
														Subtotal = $693,242

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	8/20/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $693,242 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	7/23/2024	NON-COMPETING CONTINUATION	$693,242
														Subtotal = $693,242

Issue Date FY: 2023 ( Subtotal = $707,732 )
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	7/7/2023	NON-COMPETING CONTINUATION	$707,732
														Subtotal = $707,732

Issue Date FY: 2022 ( Subtotal = $707,732 )
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/30/2022	NEW	$707,732
														Subtotal = $707,732

Grand Total All Awards = $2,801,948

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AQP4 and glymphatic function in post-stroke recovery

Award Number: R01NS124206

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: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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