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RUNX3 in Vascular Wall Remodeling

Award Number: R01HL166906
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/05/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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RUNX3 in Vascular Wall Remodeling - Project Summary Vascular smooth muscle cell (VSMC) phenotypic modulation, a phenotypic switch from a differentiated contractile phenotype to a proliferative phenotype, contributes to vascular remodeling and the development of diverse vascular diseases such as atherosclerosis, hypertension, and restenosis following angioplasty. However, the molecular mechanisms that control VSMC phenotypic modulation are poorly understood. Our exciting preliminary data strongly support a novel role of Runt-related transcription factor 3 (RUNX3) in VSMC phenotypic modulation. RUNX3 belongs to the ‘Runt domain’ family of transcription factors that act as regulators of gene expression in several important developmental pathways. We found that RUNX3 expression is significantly increased by platelet-derived growth factor-BB (PDGF-BB), a potent stimulator of VSMC phenotypic modulation. Knockdown of RUNX3 reversed PDGF-BB-inhibited expression of SMC contractile markers. In addition, RUNX3 knockdown blocked PDGF-BB-induced VSMC proliferation. These data demonstrate that RUNX3 is essential for PDGF-BB-induced VSMC phenotypic modulation and cell proliferation in vitro. In addition, RUNX3 overexpression blocked myocardin-induced α-SMA expression and promoter activity, suggesting that RUNX3 regulates VSMC contractile marker expression through myocardin/SRF signaling. RUNX3 knockdown also inhibited PDGF-BB induced expression of c-Myc, a crucial driver of VSMC proliferation. The PDGF-BB-induced activation of NF-κB and phosphorylation of GSK3β, important pathways in regulating c-Myc levels, were adversely affected by RUNX3 knockdown. RUNX3 expression was activated in the media and neointima VSMCs following the left common carotid artery injury in C57BL/6 mice. RUNX3 deficiency (RUNX3-/-) dramatically inhibited injury-induced neointima formation, suggesting that RUNX3 plays a critical role in injury-induced neointima formation and vascular remodeling in vivo. These data together strongly support a novel hypothesis that RUNX3 induces VSMC phenotypic modulation by suppressing VSMC contractile marker expression and promotes VSMC proliferation via c-Myc, leading to neointima formation/vascular remodeling, which will be tested by three Specific Aims. Aim 1: Determine the molecular mechanisms underlying RUNX3 function in modulating VSMC phenotype by testing the hypothesis that RUNX3 regulates VSMC phenotypic modulation via suppressing myocardin/SRF-mediated transcriptional activation of VSMC marker genes. Aim 2: Test the hypothesis that RUNX3 upregulates c-Myc expression through NF-κB and GSK3β/β-catenin signaling to promote VSMC proliferation. Aim 3: Test whether RUNX3 is essential for carotid artery ligation/wire injury-induced vascular remodeling using global, VSMC-specific, and endothelial cell-specific RUNX3 knockout mice. Taken together, this project will shed new lights on the pathogenesis of vascular remodeling after vessel injury, which may ultimately lead to the identification of novel targets for therapeutic treatment of various cardiovascular diseases related to vascular remodeling.


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 = $412,199 )
2026	2026	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER	11937 US HIGHWAY 271	TYLER	TX	75708	SMITH	USA	Cardiovascular Diseases Research	000	3	2/18/2026	NON-COMPETING CONTINUATION	$412,199
														Subtotal = $412,199

Issue Date FY: 2025 ( Subtotal = $441,861 )
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER	11937 US HIGHWAY 271	TYLER	TX	75708	SMITH	USA	Cardiovascular Diseases Research	001	2	8/8/2025	NON-COMPETING CONTINUATION	$44,186
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER	11937 US HIGHWAY 271	TYLER	TX	75708	SMITH	USA	Cardiovascular Diseases Research	000	2	1/13/2025	NON-COMPETING CONTINUATION	$397,675
														Subtotal = $441,861

Issue Date FY: 2024 ( Subtotal = $497,010 )
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER	11937 US HIGHWAY 271	TYLER	TX	75708	SMITH	USA	Cardiovascular Diseases Research	002	1	8/14/2024	SUPPLEMENT FOR EXPANSION	$42,510
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER	11937 US HIGHWAY 271	TYLER	TX	75708	SMITH	USA	Cardiovascular Diseases Research	000	1	1/4/2024	NEW	$410,275
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER	11937 US HIGHWAY 271	TYLER	TX	75708	SMITH	USA	Cardiovascular Diseases Research	001	1	6/17/2024	NEW	$44,225
														Subtotal = $497,010

Grand Total All Awards = $1,351,070

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RUNX3 in Vascular Wall Remodeling

Award Number: R01HL166906

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/05/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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