Tuesday, June 24, 2025 6/24/2025

The Wnt7a/ROR2 axis in the pathogenesis of pulmonary arterial hypertension

Award Number: R01HL134776
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2017
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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The Wnt7a/ROR2 axis in the pathogenesis of pulmonary arterial hypertension - Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by abnormally elevated pulmonary pressures and right ventricular (RV) failure. Inappropriate angiogenesis is a key pathological feature of PAH associated with endothelial dysfunction and progressive loss of pulmonary and RV microvessels. Angiogenesis is the process by which new vessels arise from existing vessels and is mainly driven by VEGF signaling. In response to VEGF-A, endothelial cells differentiate into tip cells, highly motile cells that direct vessel sprouting and elongation. Our previous R01 was built on the hypothesis that tip cell formation by PMVECs requires crosstalk between the VEGF and the Wnt/planar cell polarity (Wnt/PCP), a pathway responsible for coordinating cell movements during tissue morphogenesis. We demonstrated that Wnt/PCP activation in PMVECs is driven by the interaction between the ligand Wnt7a and ROR2, a tyrosine kinase receptor that phosphorylates residues in the endothelial VEGFR2 cytoplasmic domain to augment VEGF signaling output. We found that, compared to healthy donors, tip cell formation and angiogenesis in response to VEGF-A was significantly reduced in pulmonary microvascular endothelial cells (PMVEC) from PAH patients. Most importantly, supplementation with recombinant Wnt7a or restoration of ROR2 expression in PAH PMVECs results in recovery of the VEGF-A response, leading us to conclude that Wnt7a/ROR2 signaling is required for appropriate VEGF signaling activation and angiogenic response in PMVECs. This renewal will focus on elucidating the transcriptional and epigenetic mechanisms that regulate Wnt7a/ROR2 expression in healthy and PAH PMVECs (Aim 1), how interaction between ROR2 and integrins is required to establish a functional lung endothelial barrier (Aim 2), and the critical role of Wnt7a/ROR2 as a key pro- angiogenic mechanism that supports compensatory angiogenesis during RV adaptation to PAH (Aim 3). The studies in this renewal will confirm the role of Wnt7a/ROR2 signaling as a master regulator of cardiopulmonary angiogenesis and demonstrate the therapeutic potential of restoring Wnt7a/ROR2 signaling to prevent small vessel loss and improve RV function in 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 = $363,504 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	000	9	2/27/2025	NON-COMPETING CONTINUATION	$363,504
2025	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	8	6/5/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $363,504

Issue Date FY: 2024 ( Subtotal = $598,182 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	001	8	6/25/2024	NON-COMPETING CONTINUATION	$39,343
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	002	8	8/30/2024	SUPPLEMENT FOR EXPANSION	$116,227
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	000	8	3/8/2024	NON-COMPETING CONTINUATION	$442,612
														Subtotal = $598,182

Issue Date FY: 2023 ( Subtotal = $652,269 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	004	7	7/19/2023	SUPPLEMENT FOR EXPANSION	$116,227
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	003	7	6/15/2023	NON-COMPETING CONTINUATION	$536,042
2023	2022	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	002	6	4/12/2023	COMPETING CONTINUATION	$90
2023	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	6	10/13/2022	SUPPLEMENT FOR EXPANSION	$0
2023	2021	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	001	5	4/12/2023	NON-COMPETING CONTINUATION	-$90
														Subtotal = $652,269

Issue Date FY: 2022 ( Subtotal = $648,884 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	001	6	4/14/2022	COMPETING CONTINUATION	$577,149
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	002	6	8/20/2022	SUPPLEMENT FOR EXPANSION	$71,735
2022	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	000	5	3/22/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $648,884

Issue Date FY: 2021 ( Subtotal = $547,731 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	000	5	2/1/2021	NON-COMPETING CONTINUATION	$492,957
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	001	5	5/15/2021	NON-COMPETING CONTINUATION	$54,774
														Subtotal = $547,731

Issue Date FY: 2020 ( Subtotal = $528,319 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	000	4	3/17/2020	NON-COMPETING CONTINUATION	$528,319
														Subtotal = $528,319

Issue Date FY: 2019 ( Subtotal = $556,650 )
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	000	3	2/1/2019	NON-COMPETING CONTINUATION	$556,650
														Subtotal = $556,650

Issue Date FY: 2018 ( Subtotal = $508,800 )
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	001	2	5/5/2018	NON-COMPETING CONTINUATION	$10,177
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	000	2	1/22/2018	NON-COMPETING CONTINUATION	$498,623
														Subtotal = $508,800

Issue Date FY: 2017 ( Subtotal = $513,370 )
2017	2017	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Lung Diseases Research	000	1	1/10/2017	NEW	$513,370
														Subtotal = $513,370

Grand Total All Awards = $4,917,709

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The Wnt7a/ROR2 axis in the pathogenesis of pulmonary arterial hypertension

Award Number: R01HL134776

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2017

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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