# Unraveling the Mechanisms of Alcohol-Induced Blood-Brain Barrier Disruption: A Focus on Lysophosphatidic Acid Signaling and Endothelial Cells.

> **NIH NIH R01** · LOUISIANA STATE UNIV HSC SHREVEPORT · 2024 · $328,500

## Abstract

Alcohol consumption is a major risk factor for cerebrovascular complications and neuroinflammation, yet the
underlying mechanism of alcohol-induced cerebrovascular damage remains unclear. Recent studies suggest
that lysophosphatidic acid (LPA) plays a role in blood-brain barrier (BBB) dysfunction through Rho kinase
signaling. This proposal presents evidence that heavy alcohol consumption (HAC) enhances cerebrovascular
autotaxin levels and decreases lipid phosphate phosphatase-3 (LPP3) expression in brain microvascular
endothelial cells, leading to increased LPA signaling in the cerebrovasculature. Reactive oxygen species (ROS)
increase in the cerebrovasculature following HAC, promoting autotaxin expression through the redox-sensitive
transcription factor NFAT and suppressing LPP3 through miR-92a expression. The proposal aims to investigate
the role of autotaxin and LPP3 expression in HAC using cellular, mitochondrial, pharmacological, and molecular
biological approaches. The proposed studies will test the hypothesis that the LPA axis critically regulates
mitochondrial redox balance, endothelial activation, and neuroinflammation via aggravating BBB damage in
HAC. The three specific aims include assessing the effect of alcohol on mitochondrial function and redox
balance, evaluating the ability of LPP3 to regulate the alcohol-LPA axis on BBB and neuroinflammation, and
assessing the neuroprotective effect of autotaxin blockade to mitigate the impact of HAC in the
cerebrovasculature. This proposal presents the first evidence that heavy alcohol consumption (HAC) enhances
cerebrovascular LPA signaling, leading to neuroinflammation via aggravating BBB damage, and suggests
autotaxin inhibition as a potential therapy for alcohol-induced cerebrovascular damage and LPA signaling. The
findings of this study could improve our understanding of the mechanism underlying alcohol-induced
cerebrovascular injury and provide a foundation for developing targeted therapies to treat these conditions.

## Key facts

- **NIH application ID:** 10975525
- **Project number:** 1R01AA031465-01A1
- **Recipient organization:** LOUISIANA STATE UNIV HSC SHREVEPORT
- **Principal Investigator:** Manikandan Panchatcharam
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $328,500
- **Award type:** 1
- **Project period:** 2024-08-20 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10975525

## Citation

> US National Institutes of Health, RePORTER application 10975525, Unraveling the Mechanisms of Alcohol-Induced Blood-Brain Barrier Disruption: A Focus on Lysophosphatidic Acid Signaling and Endothelial Cells. (1R01AA031465-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10975525. Licensed CC0.

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