Saturday, October 18, 2025 10/18/2025

Paracrine Action of BMP3 in Pulmonary Hypertension

Award Number: R01HL160963
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Paracrine Action of BMP3 in Pulmonary Hypertension - PROJECT ABSTRACT/SUMMARY Paracrine Action of BMP3 in Pulmonary Hypertension Pulmonary arterial hypertension (PAH) is a severe vascular disease characterized by persistent precapillary pulmonary hypertension, leading to right heart failure and death. Despite intense research in the last decades PH remains an incurable disease with a high morbidity and mortality. New directions and therapies to improve understanding and treatment of PAH are desperately needed. Although evidence demonstrates the importance of the Bone Morphogenetic Protein (BMP) signaling pathway in PAH, our current understanding of the exact pathophysiological role of several members of this pathway remains limited. In this R01 we propose detailed functional and mechanistic studies to understand the role of BMP3 in PAH. We hypothesize that PASMC-derived BMP3 inhibits PAEC dysfunction and pathological pulmonary vascular remodeling. Based on robust preliminary studies, we propose testing this central hypothesis with 3 specific aims. Aim 1 will define BMP3 regulation in PAH and its effects in vitro. We will assess the levels of pulmonary BMP3 levels and circulating BMP3 levels in lung and serum of patients with clinical PAH and of PAH-diseased animals. We will also determine whether sex affects pulmonary BMP3 expression in humans and rodents, and we will investigate the effect of PASMC-derived BMP3 on PAEC function in cocultures of PASMCs and PAECs isolated from non-PAH and PAH patients. Aim 2 will characterize the in vivo effects of cell-specific BMP3 deletion and of BMP3 upregulation. We will provide a detailed characterization of the cardiopulmonary phenotypes of SMC- and EC-specific BMP3 KO mice. We will also examine the effects of exogenous recombinant BMP3 on PAH in the Sugen/Hypoxia model in rats. Using a novel approach, which we have demonstrated to be highly specific and efficient for protein overexpression in the lung (i.e. chemically modified mRNAs (modRNAs)), we will assess whether BMP3 modRNA reverses PAH in the Sugen/Hypoxia model in rats. Aim 3 will dissect the molecular mechanisms of BMP3. We will perform a series of in vitro and in vivo studies to determine the mechanism(s) of BMP3 regulation and to define BMP3 mechanism(s) of action. Promoter activity assays, co-immunoprecipitation experiments, GST pull down assays, quantitative PCR measurements and western blot analyses will determine the pathways implicated in BMP3 signals. Cocultures of PASMCs and PAECs and lungs from BMP3-KO mice and from rats overexpressing BMP3 in vivo will determine the pathways implicated in BMP3 signals.


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 = $430,141 )
2025	2025	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Lung Diseases Research	000	4	8/27/2025	NON-COMPETING CONTINUATION	$430,141
														Subtotal = $430,141

Issue Date FY: 2024 ( Subtotal = $421,539 )
2024	2024	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Lung Diseases Research	000	3	8/1/2024	NON-COMPETING CONTINUATION	$421,539
														Subtotal = $421,539

Issue Date FY: 2023 ( Subtotal = $440,341 )
2023	2023	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Lung Diseases Research	001	2	7/28/2023	NON-COMPETING CONTINUATION	$440,341
2023	2022	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Lung Diseases Research	000	1	11/4/2022	NEW	$0
														Subtotal = $440,341

Issue Date FY: 2022 ( Subtotal = $473,502 )
2022	2022	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Lung Diseases Research	000	1	8/15/2022	NEW	$473,502
														Subtotal = $473,502

Grand Total All Awards = $1,765,523

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Paracrine Action of BMP3 in Pulmonary Hypertension

Award Number: R01HL160963

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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