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SOX17/RUNX1 Axis Regulates Endothelial Cell Fate in the Pathogenesis of Pulmonary Arterial Hypertension

Award Number: R01HL158841
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/25/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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SOX17/RUNX1 Axis Regulates Endothelial Cell Fate in the Pathogenesis of Pulmonary Arterial Hypertension - Project Summary/Abstract: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by an obliterative vasculopathy of the distal pulmonary circulation. Adverse structural remodeling and increased pulmonary vascular resistance result in cardiac hypertrophy and ultimately failure of the right ventricle, with annual mortality averaging 10%. Current therapies can improve symptoms and delay disease progression, but there is no cure. There is a critical need to develop new therapies that effectively halt and reverse the disease by targeting the cellular and molecular mechanisms underlying the pathophysiology of PAH. In Sox17 mutant PAH patients, we postulate that loss-of-function mutations in the Sox17 gene result in insufficient upregulation of Sox17 during normal reparative responses to vascular injury allowing increased RUNX1 signaling to drive aberrant angiogenesis. Thus, our central hypothesis is that loss of repression of Runx1 by endothelial SOX17 predisposes to the development of PAH through impaired arterial endothelial differentiation and aberrant angiogenesis. To test our hypothesis, we plan the following specific aims: Aim 1. Determine if endothelial SOX17 deficiency leads to higher susceptibility of developing PAH. Aim 2. Determine if SOX17/RUNX1 imbalance leads to impaired arterial differentiation and aberrant angiogenesis following SuHx-PH induction. Aim 3: Determine if Sox17 mutant PAH patient iPSC-derived ECs have impaired arterial differentiation and defective angiogenic capability.


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 = $410,000 )
2025	2025	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Lung Diseases Research	000	4	7/15/2025	NON-COMPETING CONTINUATION	$410,000
														Subtotal = $410,000

Issue Date FY: 2024 ( Subtotal = $410,000 )
2024	2024	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Lung Diseases Research	000	3	6/14/2024	NON-COMPETING CONTINUATION	$410,000
														Subtotal = $410,000

Issue Date FY: 2023 ( Subtotal = $410,000 )
2023	2023	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Lung Diseases Research	001	2	6/16/2023	NON-COMPETING CONTINUATION	$410,000
2023	2022	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Lung Diseases Research	000	1	1/27/2023	NEW	$0
														Subtotal = $410,000

Issue Date FY: 2022 ( Subtotal = $410,000 )
2022	2022	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Lung Diseases Research	000	1	8/25/2022	NEW	$410,000
														Subtotal = $410,000

Grand Total All Awards = $1,640,000

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SOX17/RUNX1 Axis Regulates Endothelial Cell Fate in the Pathogenesis of Pulmonary Arterial Hypertension

Award Number: R01HL158841

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/25/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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