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Targeting the Hippo signaling at the Blood-brain barrier for therapy of ischemic stroke

Award Number: R01NS105787
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: 08/16/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Targeting the Hippo signaling at the Blood-brain barrier for therapy of ischemic stroke - Abstract Although considerable efforts have been made focusing on the neuronal/glial injury to find new targets for stroke therapy, no success has been achieved. Therapy of stroke is still limited to preventive treatments and to acute thrombolysis and symptomatic control of intracranial pressure. Pathological changes at the level of brain endothelium plays an important role in progression of brain diseases. However, the approaches to modulate the BBB function for therapy are still very limited. Recently, studies have shown that the YES-associated protein (YAP) and its paralog TAZ (transcriptional co-activator with PDZ-binding motif), the transcriptional coactivators of the Hippo signaling pathway, promote endothelial cell proliferation, migration and angiogenesis. YAP/TAZ also plays a role in regulating formation and integrity of tight-junction, which indicates its possible role in tight-junction of the BBB. Our central hypothesis is that YAP/TAZ promotes brain angiogenesis and plays an important role in maintaining the BBB integrity, and YAP/TAZ-exosome has a therapeutic effect against brain ischemia/reperfusion injury by promoting repair of the BBB and restoration of the BBB integrity. The present proposal aims to elucidate the role of YAP/TAZ in regulating the BBB function, to evaluate protective effect of YAP/TAZ on brain ECs and the BBB against ischemia/reperfusion injury, and to develop a novel approach, YAP/TAZ-exosome, for treatment of ischemic stroke. We will use the ischemic stroke model in vitro and in vivo to test our hypothesis We expect that YAP/TAZ promotes brain ECs proliferation, migration and angiogenesis, and over- expression of YAP/TAZ and YAP/TAZ-Exosomes promote the BBB repair after ischemic injury, which leads to improvement of ischemic stroke outcomes shown as improved behavior outcome, less inflammatory responses and the BBB leakage in the brain etc. The proposed study is highly significant and innovative because it will advance our understanding of the role of YAP/TAZ in regulating the BBB function and pathophysiology of the BBB under ischemic stroke. The proposed project will explore YAP/TAZ as a novel therapeutic target for ischemic stroke therapy, exosome as a novel delivery carrier, and the brain EC as a novel site for brain disease therapy and brain drug delivery. Furthermore, the proposed therapeutic approach could be broadly applied for therapy of diseases affecting the BBB and central nervous system. Therefore, the overall impact of the project is highly significant in advancing drug discovery that targets the brain endothelium for brain disease therapy.


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 = -$329,769 )
2026	2023	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/15/2026	NON-COMPETING CONTINUATION	-$329,769
														Subtotal = -$329,769

Issue Date FY: 2024 ( Subtotal = -$10,198 )
2024	2023	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	9/11/2024	NON-COMPETING CONTINUATION	-$10,198
														Subtotal = -$10,198

Issue Date FY: 2023 ( Subtotal = $339,964 )
2023	2023	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	8/10/2023	NON-COMPETING CONTINUATION	$339,964
														Subtotal = $339,964

Issue Date FY: 2022 ( Subtotal = $339,964 )
2022	2022	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/14/2022	NON-COMPETING CONTINUATION	$339,964
														Subtotal = $339,964

Issue Date FY: 2021 ( Subtotal = $339,964 )
2021	2021	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	7/5/2021	NON-COMPETING CONTINUATION	$339,964
														Subtotal = $339,964

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	2/8/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$92,669
2020	2019	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	2	7/15/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2020	2019	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/7/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2020	2018	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	2/8/2020	NEW	-$92,669
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $343,674 )
2019	2019	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	9/18/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$343,674
2019	2018	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/18/2019	NEW	$0
														Subtotal = $343,674

Issue Date FY: 2018 ( Subtotal = $356,435 )
2018	2018	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/21/2018	NEW	$356,435
														Subtotal = $356,435

Grand Total All Awards = $1,380,034

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Targeting the Hippo signaling at the Blood-brain barrier for therapy of ischemic stroke

Award Number: R01NS105787

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: 08/16/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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