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Molecular pathogenesis of pulmonary arterial hypertension

Award Number: R01HL153915
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Molecular pathogenesis of pulmonary arterial hypertension - PROJECT SUMMARY/ABSTRACT Pulmonary Arterial Hypertension (PAH) is a rare disease characterized by the progressive remodeling of pulmonary arteries (PAs). It is incurable and leads to death from right ventricular heart failure in 3 years if untreated. Heterozygous mutations of the bone morphogenetic protein type 2 receptor gene (BMPR2) are the leading genetic cause of both heritable and non-heritable PAH. Compared to patients without BMPR2 mutations, PAH patients with BMPR2 mutations develop a more severe form of PAH at least 10 years earlier. Despite the progress in understanding the molecular and cellular processes mediating occlusive remodeling of PAs as a result of BMPR2 mutations, a targeted therapy does not yet exist, and BMPR2 carrier patients remain at high risk of requiring transplantation and succumbing to the disease. There is a dire need of novel therapies for BMPR2 mutation patients. Our studies demonstrated increased DNA damage in both idiopathic- and heritable-PAH patients, suggesting genotoxic stress is a risk factor for PAH, but significant knowledge gaps persist, as follows: (i) whether the loss of genome integrity is the cause or the consequence of PAH, (ii) the cell type in which DNA damage occur, (iii) a potential link between BMPR2 mutations and DNA damage, and (iv) the molecular mechanism of DNA damage in PAH. We found that BMPR2 and its downstream signaling pathway are essential to protect genome integrity in pulmonary artery endothelial cells (PAECs), and they act by maintaining a key component of the DNA repair pathway: Rad51. Inactivation of BMPR2 results in reduction of Rad51, leading to accumulation of DNA damage in PAECs. Attenuation of Rad51 was measured in the endothelium of both animal models of PAH and human patients. On the contrary, activation of the BMPR2 signaling pathway by BMP9 restores Rad51 and prevents the accumulation of DNA damage in PAECs. The main hypothesis we will test is that PAECs undergoing genotoxic stress develop a pathological remodeling and PAH. The objective of this application is to develop a strategy to restore the DNA repair system in PAECs and prevent or inhibit the progression of vascular remodeling, as a novel therapy for PAH with a defective BMP signal. The forthcoming results from this application will provide important insights into developing a novel therapeutic strategy for 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: 2024 ( Subtotal = $756,015 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Lung Diseases Research	001	4	6/20/2024	NON-COMPETING CONTINUATION	$61,714
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	4	1/24/2024	NON-COMPETING CONTINUATION	$694,301
														Subtotal = $756,015

Issue Date FY: 2023 ( Subtotal = $779,519 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	3	1/31/2023	NON-COMPETING CONTINUATION	$779,519
														Subtotal = $779,519

Issue Date FY: 2022 ( Subtotal = $795,669 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	001	2	6/14/2022	NON-COMPETING CONTINUATION	$79,565
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	2	2/2/2022	NON-COMPETING CONTINUATION	$716,104
														Subtotal = $795,669

Issue Date FY: 2021 ( Subtotal = $803,744 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	001	1	6/26/2021	NEW	$80,373
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	1	4/30/2021	NEW	$723,371
														Subtotal = $803,744

Grand Total All Awards = $3,134,947

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Molecular pathogenesis of pulmonary arterial hypertension

Award Number: R01HL153915

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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