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YAP1, neointima formation, and blood pressure regulation

Award Number: R00HL153896
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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YAP1, neointima formation, and blood pressure regulation - PROJECT SUMMARY Vascular smooth muscle cell (VSMC) phenotypic modulation is central to the etiologies of multiple vascular wall diseases. In post-angioplasty restenosis and atherosclerosis, VSMCs acquire a proliferative/migratory phenotype leading to neointima formation. In contrast, hypertension is largely caused by increased vascular resistance that is attributed to exaggerated VSMC contraction and vascular remodeling. Identification of the key players that regulate VSMC proliferation and contraction is critical for further understanding of the underlying mechanisms of VSMC-driven vascular wall diseases and also for developing novel therapeutic approaches. We have previously demonstrated that the transcription co-factor yes-associated protein 1 (YAP1) promotes VSMC proliferation. Yet, the role and underlying mechanisms of YAP1 in neointima formation in vivo remain unclear. Furthermore, recent genome-wide association studies (GWAS) have identified a loss-of-function single nucleotide polymorphism (SNP) in YAP1 gene locus that was unexpectedly associated with lower blood pressure, suggesting a novel role of YAP1 in blood pressure regulation. The overarching goal of this proposal is to determine the role of YAP1 in regulating both VSMC proliferation and contraction/hypertension. Novel preliminary data in this proposal include 1) YAP1 expression is upregulated after arterial injury and correlates with VSMC proliferation in vivo, 2) YAP1, in association with TEA domain transcription factor 1 (TEAD1), induces platelet-derived growth factor receptor beta (PDGFRb), a putative novel YAP1 target gene that regulates VSMC phenotype, 3) SM-specific Yap1 knockout mice exhibit a hypotensive phenotype and an attenuated response to vasoconstrictors in isolated vessels, and 4) silencing YAP1 in VSMCs inhibited protein kinase C alpha (PRKCa) signaling and impaired actin polymerization, which are key for VSMC contraction. Three specific aims are proposed to test the central hypothesis that YAP1 induces VSMC proliferation and contraction to drive neointima formation and hypertension, respectively. K99 Aim 1. Test the hypothesis that YAP1 induces PDGFRb to promote VSMC proliferation and enhance injury-induced neointima formation in vivo. R00 Aim 2. Test the hypothesis that YAP1 activates PRKCa signaling and promotes actin polymerization to enhance VSMC contraction. R00 Aim 3. Test the hypothesis that VSMC-expressed YAP1 underlies experimental hypertension. Completion of the proposed studies will provide novel insights into the mechanisms regulating VSMC phenotypic modulation and blood pressure regulation and will determine if inhibiting YAP1 is an attractive novel therapeutic strategy for ameliorating both occlusive vascular diseases and hypertension. Additional conceptual and experimental training in hypertension-related research during the K99 phase will help the applicant pursue an independent career and transform this proposal into an R01 application during the R00 phase.


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 = $249,000 )
2025	2025	UNIVERSITY OF TOLEDO	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Cardiovascular Diseases Research	001	5	9/23/2025	NON-COMPETING CONTINUATION	$0
2025	2025	UNIVERSITY OF TOLEDO	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Cardiovascular Diseases Research	000	5	11/27/2024	NON-COMPETING CONTINUATION	$249,000
														Subtotal = $249,000

Issue Date FY: 2024 ( Subtotal = $249,000 )
2024	2024	UNIVERSITY OF TOLEDO, THE	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Cardiovascular Diseases Research	000	4	12/4/2023	NON-COMPETING CONTINUATION	$224,101
2024	2024	UNIVERSITY OF TOLEDO	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Cardiovascular Diseases Research	001	4	6/26/2024	NON-COMPETING CONTINUATION	$24,899
														Subtotal = $249,000

Issue Date FY: 2023 ( Subtotal = $292,529 )
2023	2023	UNIVERSITY OF TOLEDO, THE	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Cardiovascular Diseases Research	001	3	7/25/2023	EXTENSION WITH OR WITHOUT FUNDS	$43,529
2023	2023	UNIVERSITY OF TOLEDO, THE	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Cardiovascular Diseases Research	000	3	11/23/2022	EXTENSION WITH OR WITHOUT FUNDS	$249,000
														Subtotal = $292,529

Grand Total All Awards = $790,529

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YAP1, neointima formation, and blood pressure regulation

Award Number: R00HL153896

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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