Tuesday, July 1, 2025 7/1/2025

Galectin-3: A mediator of vascular remodeling in pulmonary arterial hypertension

Award Number: R01HL125926
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2016
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Galectin-3: A mediator of vascular remodeling in pulmonary arterial hypertension - PROJECT SUMMARY Pulmonary Arterial Hypertension (PAH) is a progressively debilitating and eventually lethal disease, whereby only the symptoms are treated by current therapeutics. A defining characteristic of PAH is the excessive cellular proliferation and remodeling of pulmonary arteries (PA) that results in increased vascular resistance and stiffness, and eventually failure of the right ventricle and death. PAH has a survival time of less than five-years post diagnosis, and current treatment strategies are self-limiting in that they do not sufficiently prolong survival time or reverse the pathologic vascular remodeling. In the previous funding period we established an important role for Galectin-3 (Gal-3) in mediating aberrant pulmonary vascular remodeling, and demonstrated that Gal-3 knockout rats are protected from PAH and further showed the ability of pharmacological inhibitors of Gal-3 to prevent and reverse established PAH. Gal-3 expression was also found in pulmonary arterial smooth muscle cells (PASMC), where it promoted proliferation, migration and resistance to apoptosis. In preliminary data for this competitive renewal, we find that HIF2α robustly upregulates Gal-3 expression. Along these lines, we have uncovered a novel HIF2α binding site on the LGALS3 promoter, and using a capsid modified AAV2 that specifically targets lung endothelial cells (EC), we also show that increased expression of HIF2α in PAEC in vivo increases Gal-3 and promotes pulmonary hypertension in mice. In co-culture experiments we show that upregulation of HIF2α in the endothelium can promote increased Gal-3 expression in the underlying PASMC and enhance proliferation. We also identified DNA methylation as a major regulator of Gal-3 expression as the DNA methyltransferase, DNMT3A was downregulated in PAH. Further, silencing DNMT3A increased Gal-3 expression, and a dCas9-DNMT3A fusion directed to the Gal-3 promoter, decreased Gal-3 expression. In vitro, the combination of hypoxia and loss of DNA methylation synergize to drive high level Gal-3 expression, and NEAT1 is a recently described hypoxia regulated lncRNA that regulates smooth muscle cell phenotype and proliferation. Towards this end, we found that NEAT1 expression is increased in human PAH lung as well as in PA from MCT rats and is regulated by Gal-3 in PASMC. Our long term objectives are to 1. Determine the cell specific role of Gal-3 in mediating vascular remodeling and PAH, 2. Investigate the role of DNA methylation and DNMT3A in regulating Gal-3 expression and synergy with HIF2, and 3. Determine whether Gal-3 regulation of NEAT1 in PASMC contributes to PAH.


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 = $630,630 )
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Lung Diseases Research	000	8	1/22/2025	NON-COMPETING CONTINUATION	$630,630
														Subtotal = $630,630

Issue Date FY: 2024 ( Subtotal = $686,685 )
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Lung Diseases Research	000	7	1/26/2024	NON-COMPETING CONTINUATION	$630,630
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Lung Diseases Research	001	7	6/20/2024	NON-COMPETING CONTINUATION	$56,055
														Subtotal = $686,685

Issue Date FY: 2023 ( Subtotal = $700,700 )
2023	2023	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Lung Diseases Research	000	6	1/24/2023	NON-COMPETING CONTINUATION	$700,700
														Subtotal = $700,700

Issue Date FY: 2022 ( Subtotal = $700,700 )
2022	2022	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Lung Diseases Research	000	5	2/10/2022	COMPETING CONTINUATION	$700,700
														Subtotal = $700,700

Issue Date FY: 2021 ( Subtotal = -$2,100 )
2021	2019	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Lung Diseases Research	000	4	2/19/2021	NON-COMPETING CONTINUATION	-$2,100
														Subtotal = -$2,100

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Lung Diseases Research	000	4	3/18/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $538,001 )
2019	2019	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Lung Diseases Research	000	4	1/18/2019	NON-COMPETING CONTINUATION	$538,001
														Subtotal = $538,001

Issue Date FY: 2018 ( Subtotal = $538,001 )
2018	2018	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST # CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	3	1/22/2018	NON-COMPETING CONTINUATION	$527,240
2018	2018	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST # CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	001	3	5/12/2018	NON-COMPETING CONTINUATION	$10,761
														Subtotal = $538,001

Issue Date FY: 2017 ( Subtotal = $538,001 )
2017	2017	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST # CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	2	1/19/2017	NON-COMPETING CONTINUATION	$538,001
														Subtotal = $538,001

Issue Date FY: 2016 ( Subtotal = $538,001 )
2016	2016	GEORGIA REGENTS RESEARCH INSTITUTE INC	1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cardiovascular Diseases Research	000	1	1/12/2016	NEW	$538,001
														Subtotal = $538,001

Grand Total All Awards = $4,868,619

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Galectin-3: A mediator of vascular remodeling in pulmonary arterial hypertension

Award Number: R01HL125926

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2016

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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