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GPR4 in blood brain barrier dysfunction in brain ischemia

Award Number: R01NS124722
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/12/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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GPR4 in blood brain barrier dysfunction in brain ischemia - 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.


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 = $382,500 )
2026	2026	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	6/3/2026	NON-COMPETING CONTINUATION	$382,500
														Subtotal = $382,500

Issue Date FY: 2025 ( Subtotal = $382,500 )
2025	2025	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	4	6/13/2025	NON-COMPETING CONTINUATION	$382,500
2025	2023	THE CURATORS OF THE UNIVERSITY OF MISSOURI	118 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	4/11/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2023	THE CURATORS OF THE UNIVERSITY OF MISSOURI	118 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	2	6/5/2025	NON-COMPETING CONTINUATION	$0
2025	2023	THE CURATORS OF THE UNIVERSITY OF MISSOURI	118 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/11/2025	NON-COMPETING CONTINUATION	-$350,000
2025	2023	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	4/11/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$350,000
														Subtotal = $382,500

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	THE CURATORS OF THE UNIVERSITY OF MISSOURI	118 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	7/11/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2023	THE CURATORS OF THE UNIVERSITY OF MISSOURI	118 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	7/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $778,466 )
2023	2023	UNIVERSITY OF MISSOURI SYSTEM	1011 E 51ST ST	KANSAS CITY	MO	64110	JACKSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	6/12/2023	SUPPLEMENT FOR EXPANSION	$391,250
2023	2023	UNIVERSITY OF MISSOURI SYSTEM	1011 E 51ST ST	KANSAS CITY	MO	64110	JACKSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/7/2023	NON-COMPETING CONTINUATION	$387,216
														Subtotal = $778,466

Issue Date FY: 2022 ( Subtotal = $387,295 )
2022	2022	UNIVERSITY OF MISSOURI SYSTEM	5100 ROCKHILL RD	KANSAS CITY	MO	64110	JACKSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/23/2022	NEW	$387,295
														Subtotal = $387,295

Grand Total All Awards = $1,930,761

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GPR4 in blood brain barrier dysfunction in brain ischemia

Award Number: R01NS124722

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/12/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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