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Combination treatment of ischemic stroke with perlecan DV and neural stem cells

Award Number: R01NS110370
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: 06/01/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Combination treatment of ischemic stroke with perlecan DV and neural stem cells - PROJECT ABSTRACT Stroke, the fifth leading cause of death and leading cause of long-term disability in the United States, has limited therapeutic options. Even with the advent of reperfusion therapies including tissue plasminogen activator (tPA) and mechanical thrombectomy, extensive injury from stroke often results from ischemia- reperfusion (IR), which damages the blood-brain barrier (BBB), the vessel network separating the brain from the circulatory system. IR causes biphasic openings in the BBB, the first occurring within several hours of insult and the second at 24-74 hours after stroke. The latter is generally irreversible and, thus, the most damaging. Clinically, stem cell therapy offers great promise for treating stroke, but is currently aiming for stroke rehabilitation by delivering cells during the recovery (not subacute) phase. Here, we propose a novel approach to administer neural stem cells (NSCs) in the sub-acute phase to limit early-stage BBB injuries, an outcome that would protect against the second phase of stroke damage. We base this proposal on our extensive and novel preliminary and pilot data derived from a stroke mouse model showing that human(h)NSCs transplanted into the brain 24h post-IR improves neurological function and reduces BBB damage. Further, we have demonstrated that a protein fragment of the brain extracellular matrix (ECM) component perlecan, termed domain V (DV), is neuroprotective after experimental ischemic stroke, and may represent a promising new stroke therapy. Intriguingly, preliminary results also suggest that DV enhances NSC survival and differentiation in to neurons in vitro. Therefore, in this study, we will test the hypothesis that NSCs, in combination with the neuroprotective and neuroreparative protein perlecan DV, will synergistically ameliorate pathophysiology and neurological outcome in stroked mice. Ameliorating BBB damage before NSC transplantation using a neuroprotectant DV will improve the brain environment for NSC survival and allow for greater NSC efficacy. We will employ a filament MCAO/reperfusion (IR injury) mouse model that mimics ischemic stroke injuries seen in patients. Since aging is a strong risk factor for stroke, we will use both young adult and aged female and male mice, in whom neurobehavioral deficits are found to be worse. Aim 1 will determine the effects of neural stem cells and DV co-administration on sub-acute stroke injury in young adult and aged mice. Aim 2 will determine the effects of sub-acute neural stem cell delivery and DV co-administration on neuro-repair and long-term stroke recovery. Aim 3 will investigate the direct effect of perlecan DV in mechanisms of a2b1-induced NSC neuronal differentiation in vitro. This study is significant because it will generate new preclinical data that demonstrate the optimal strategy for NSC treatment, coupled with a novel neuroprotectant for ischemic stroke. The study will use innovative methods by employing and combining adjuvant pharmacological treatment (neuroprotectant) with NSCs, to improve stroke outcome.


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: 2025 ( Subtotal = $0 )
2025	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	12/6/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = -$32,605 )
2024	2023	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	005	5	8/13/2024	NON-COMPETING CONTINUATION	$0
2024	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	3/5/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$344,362
2024	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	006	6	8/13/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2024	2023	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/5/2024	NON-COMPETING CONTINUATION	-$376,967
2024	2023	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	5	7/29/2024	NON-COMPETING CONTINUATION	$39,240
2024	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	6	3/14/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2024	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	6	7/29/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$39,240
														Subtotal = -$32,605

Issue Date FY: 2023 ( Subtotal = $488,349 )
2023	2023	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	2/2/2023	NON-COMPETING CONTINUATION	$48,833
2023	2023	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/15/2022	NON-COMPETING CONTINUATION	$439,516
														Subtotal = $488,349

Issue Date FY: 2022 ( Subtotal = $484,513 )
2022	2022	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	3/28/2022	NON-COMPETING CONTINUATION	$48,450
2022	2022	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	11/19/2021	NON-COMPETING CONTINUATION	$436,063
														Subtotal = $484,513

Issue Date FY: 2021 ( Subtotal = $480,784 )
2021	2021	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	1/11/2021	NON-COMPETING CONTINUATION	$48,076
2021	2021	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/16/2020	NON-COMPETING CONTINUATION	$432,708
														Subtotal = $480,784

Issue Date FY: 2020 ( Subtotal = $476,441 )
2020	2020	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	2/11/2020	NON-COMPETING CONTINUATION	$47,644
2020	2020	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/13/2019	NON-COMPETING CONTINUATION	$428,797
														Subtotal = $476,441

Issue Date FY: 2019 ( Subtotal = $481,540 )
2019	2019	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/14/2018	NEW	$481,540
														Subtotal = $481,540

Grand Total All Awards = $2,379,022

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Combination treatment of ischemic stroke with perlecan DV and neural stem cells

Award Number: R01NS110370

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: 06/01/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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