# AQP4 and glymphatic function in post-stroke recovery

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2022 · $707,732

## Abstract

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.

## Key facts

- **NIH application ID:** 10537803
- **Project number:** 1R01NS124206-01A1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Christopher A Flask
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $707,732
- **Award type:** 1
- **Project period:** 2022-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10537803

## Citation

> US National Institutes of Health, RePORTER application 10537803, AQP4 and glymphatic function in post-stroke recovery (1R01NS124206-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10537803. Licensed CC0.

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