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Novel Therapeutic Strategies to Resolve Neurovascular Inflammation and Repair Blood-Brain Barrier Dysfunction in Epilepsy

Award Number: R01NS079507
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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View Award Abstract

Blood-brain barrier dysfunction is recognized as both a cause and consequence of seizures in epilepsy. Two key characteristics of barrier dysfunction in epilepsy include 1) neurovascular inflammation and 2) barrier leakage, both of which have been linked to seizures. In spite of increasing evidence supporting that glutamate causes blood-brain barrier dysfunction, knowledge of the associated underlying mechanisms remain to be fully defined. Moreover, therapeutic options for restoring barrier function are currently not available. Thus, there is an unmet critical need to determine how glutamate promotes blood-brain barrier inflammation and leakage and to develop targeted strategies to restore barrier function. The consequence of this unmet need is that development of novel treatments to improve seizure control in epilepsy will likely remain a clinical challenge. The long-term goal of the investigator is to contribute toward the development of mechanism-based strategies to repair blood-brain barrier dysfunction in brain diseases. The overall objective in this application is to establish the efficacy of a mechanism- based intervention to treat blood-brain barrier dysfunction in epilepsy, thereby vertically extending what has been learned under current funding. Based on preliminary data the central hypothesis of this project is that glutamate signaling mediates blood-brain barrier dysfunction and that therapeutic intervention targeting this mechanism will resolve seizure-induced neurovascular inflammation, repair barrier leakage, and reduce seizure burden. The rationale for the proposed research is that its successful completion will provide a robust framework for the continued development and clinical translation of a novel evidence-based therapeutic intervention to help treat seizures in patients with epilepsy. The hypothesis will be tested by pursuing three specific aims: 1) Identify signaling steps responsible for seizure-induced inflammation of the blood-brain barrier. 2) Determine the mechanism responsible for capillary leakage at the human blood-brain barrier, and 3) Develop a therapeutic intervention to reduce seizure burden in a chronic epilepsy model. Under Aim 1, signaling steps that lead to seizure-mediated neuroinflammation will be determined in capillaries isolated from knockout mouse models and verified in vivo. Under Aim 2, key signaling steps that trigger barrier leakage will be determined in human brain capillaries from seizure-free control individuals and from patients with epilepsy. Under Aim 3, an intervention therapy designed to repair barrier dysfunction will be developed and the therapeutic benefit of this strategy on reducing seizure burden will be evaluated in a rat chronic epilepsy model. The proposed research is innovative, because it represents a substantive departure from the status quo by shifting the focus to molecular targets at the blood-brain barrier to resolve neurovascular inflammation, restore barrier function, and improve epilepsy symptoms. The proposed research is significant because it holds the promise of a novel therapeutic approach to repair barrier dysfunction that has translational potential for clinical use to advance treatment of patients with epilepsy and other seizure disorders with underlying barrier dysfunction.


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: 2024 ( Subtotal = $553,745 )
2024	2024	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	10	4/11/2024	NON-COMPETING CONTINUATION	$39,961
2024	2024	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	3/27/2024	NON-COMPETING CONTINUATION	$513,784
														Subtotal = $553,745

Issue Date FY: 2023 ( Subtotal = $561,713 )
2023	2023	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	5/25/2023	NON-COMPETING CONTINUATION	$561,713
														Subtotal = $561,713

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	5/4/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $601,764 )
2021	2021	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	3/31/2021	NON-COMPETING CONTINUATION	$601,764
														Subtotal = $601,764

Issue Date FY: 2020 ( Subtotal = $608,819 )
2020	2020	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	6/12/2020	COMPETING CONTINUATION	$608,819
														Subtotal = $608,819

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2016	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	2/21/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2016	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	7/25/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $326,694 )
2016	2016	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	109 KINEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	6/24/2016	NON-COMPETING CONTINUATION	$326,694
														Subtotal = $326,694

Issue Date FY: 2015 ( Subtotal = $326,694 )
2015	2015	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	109 KINEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	7/6/2015	NON-COMPETING CONTINUATION	$326,694
														Subtotal = $326,694

Issue Date FY: 2014 ( Subtotal = $323,426 )
2014	2014	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	109 KINEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	4	7/4/2014	NON-COMPETING CONTINUATION	$323,426
2014	2013	UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/14/2014	NON-COMPETING CONTINUATION	-$320,863
2014	2013	UNIVERSITY OF KENTUCKY, RESEARCH FOUNDATION	109 KINEAD HALL	LEXINGTON	KY	40506	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	5/14/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$320,863
														Subtotal = $323,426

Issue Date FY: 2013 ( Subtotal = $320,863 )
2013	2013	UNIVERSITY OF MINNESOTA	UNIV GATEWAY#450/200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/21/2013	NON-COMPETING CONTINUATION	$320,863
														Subtotal = $320,863

Issue Date FY: 2012 ( Subtotal = $332,500 )
2012	2012	UNIVERSITY OF MINNESOTA	UNIV GATEWAY#450/200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/28/2012	NEW	$332,500
														Subtotal = $332,500

Grand Total All Awards = $3,956,218

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Novel Therapeutic Strategies to Resolve Neurovascular Inflammation and Repair Blood-Brain Barrier Dysfunction in Epilepsy

Award Number: R01NS079507

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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