# Astrocytes-Mediated Regulation of Wnt/b-Catenin Pathway in Ischemic Brain

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $342,344

## Abstract

PROJECT SUMMARY
 Cerebral vessel-associated astrocyte end-feet play an important role in formation and
maintenance of the blood-brain barrier (BBB), and regulation of neurovascular coupling and
cerebral blood flow (CBF). Ischemic stroke causes structural and biochemical changes of the
perivascular astrocytes, but the underlying molecular mechanisms and subsequent impact on
cerebral vessel damage/repair are not well understood. Previously, we show that in response to
ischemia and hypoxia, reactive astrocytes stimulate Na+/H+ exchanger isoform 1 protein (NHE1)
activity to counteract the acidic pHi. This leads to intracellular Na+ overload, astrocytic swelling,
and impaired glutamate uptake, which aggravates ischemic brain damage. Our recent study
shows that selective deletion of Nhe1 in astrocytes (Astro-KO) abolished ischemic stroke-
mediated astrogliosis, preserved BBB function, and reduced cerebral vessel damage in a
mouse model of focal ischemic stroke (transient middle cerebral artery occlusion). Despite the
neuroprotective effects conferred by astrocytic Nhe1 deletion in ischemic brains, the precise
molecular mechanisms involved in the process are not completely understood. Our preliminary
study reveals that Wnt signaling pathway genes are the most significantly upregulated genes in
Nhe1 Astro-KO ischemic brains. Most importantly, targeted deletion of Nhe1 in Astro-KO mice
caused elevation of Wnt 7a/b and −catenin protein, accompanied with increased expression of
tight junction protein (TJ) and preservation of TJ structures in the blood vessels after ischemic
stroke. These new findings led us to hypothesize that deletion of astrocytic Nhe1 promotes
ischemic tissue repair by Wnt/−catenin mediated signaling mechanisms. We will investigate
that increased Wnt7a/b gene expression in Nhe1 Astro-KO mice leads to 1) increased
Wnt/−catenin signaling in vascular endothelial cells, 2) improves the BBB structural and
functional integrity, and 3) promotes vascular recovery by angiogenesis and restore of the
cerebral flow regulation after ischemic stroke. Completion of three specific aims will generate
new knowledge and identify novel therapeutic agents for promoting vascular repairs after
ischemic stroke.

## Key facts

- **NIH application ID:** 10307589
- **Project number:** 5R01NS110755-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Gulnaz Begum
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $342,344
- **Award type:** 5
- **Project period:** 2019-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10307589

## Citation

> US National Institutes of Health, RePORTER application 10307589, Astrocytes-Mediated Regulation of Wnt/b-Catenin Pathway in Ischemic Brain (5R01NS110755-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10307589. Licensed CC0.

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