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

Award Number: R01AA031465
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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


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 = $338,939 )
2026	2026	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Alcohol Research Programs	001	3	6/8/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$338,939
2026	2025	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Alcohol Research Programs	000	2	5/29/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $338,939

Issue Date FY: 2025 ( Subtotal = $328,500 )
2025	2025	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Alcohol Research Programs	000	2	7/9/2025	NON-COMPETING CONTINUATION	$328,500
														Subtotal = $328,500

Issue Date FY: 2024 ( Subtotal = $328,500 )
2024	2024	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Alcohol Research Programs	000	1	8/16/2024	NEW	$328,500
														Subtotal = $328,500

Grand Total All Awards = $995,939

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

Award Number: R01AA031465

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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