# GPR4 in blood brain barrier dysfunction in brain ischemia

> **NIH NIH R01** · UNIVERSITY OF MISSOURI KANSAS CITY · 2022 · $387,295

## Abstract

ABSTRACT
Brain microvascular endothelial cells (BMEC), tightly connected through tight junctions and adhesions junctions,
provide the structural basis for the blood-brain barrier (BBB). In both human patients and animal models, BBB
disruption exhibits positive correlation with stroke outcome. Discovering novel mechanisms to protect endothelial
barrier integrity will provide important insights into better therapeutic targeting of ischemia-reperfusion-induced
neuronal injury. One prevalent process in brain ischemia is the prolonged reduction of brain pH, which implicates
protons as an important extracellular signal. In previous studies, most emphasis on brain proton signaling has
been on its role in neurons. In contrast, few studies have assessed whether acidosis alters blood-brain barrier
integrity, which is one important contributor to ischemia-induced neuronal injury. This application will focus on
GPR4, a proton-sensitive G protein-coupled receptor which exhibits abundant expression in BMEC. Using a
combination of in vivo and in vitro models, the proposed research will determine whether GPR4 mediates acid
signaling in BMEC, and identify its downstream mediator in acidotic and ischemic conditions. With genetic
manipulation and pharmacological interventions, we will determine whether deleting or inhibiting GPR4
specifically in endothelial cells attenuates ischemia-induced BMEC dysfunction and protects the brain from
ischemia-induced neuronal injury. To better understand the mechanism, the research will analyze downstream
signaling and perform unbiased analysis of transcriptome changes from acutely isolated BMEC. Lastly, this study
will use the liquid chromatography-mass spectrometry approach to determine the pharmacokinetics of a GPR4
inhibitor in brain and blood tissue. Once successfully accomplished, the study will offer GPR4 inhibition as a
novel neuroprotective approach to alleviate ischemia-induced brain injury.

## Key facts

- **NIH application ID:** 10522141
- **Project number:** 1R01NS124722-01A1
- **Recipient organization:** UNIVERSITY OF MISSOURI KANSAS CITY
- **Principal Investigator:** Xiangming Zha
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $387,295
- **Award type:** 1
- **Project period:** 2022-07-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10522141

## Citation

> US National Institutes of Health, RePORTER application 10522141, GPR4 in blood brain barrier dysfunction in brain ischemia (1R01NS124722-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10522141. Licensed CC0.

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