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METABOLIC REPROGRAMMING AND PULMONARY VASCULAR DISEASE ASSOCIATED WITH CONGENITAL HEART DISEASE RESULTING IN INCREASED PULMONARY BLOOD FLOW

Award Number: P01HL146369
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/10/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2030

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METABOLIC REPROGRAMMING AND PULMONARY VASCULAR DISEASE ASSOCIATED WITH CONGENITAL HEART DISEASE RESULTING IN INCREASED PULMONARY BLOOD FLOW - PROGRAM SUMMARY Pulmonary vascular disease (PVD) is one of the most critical complications of children born with congenital heart disease (CHD) that results in increased pulmonary blood flow (PBF). Metabolic reprogramming is increasingly recognized as a critical component of early pulmonary vascular injury and disease. Vascular morphology studies in our model demonstrate a >2-fold increase in pulmonary arterioles in Shunt compared to control lambs. This is opposed to decreased arterial counts in humans with advanced disease. This early increase in angiogenesis represents an adaptation to increased PBF. Developing a hyperproliferative, anti-apoptotic endothelial phenotype is necessary for this angiogenic response and requires a dramatic metabolic reprogramming that supplies these cells with the requisite biosynthetic precursors. A consequence of these metabolic changes is the loss of NO signaling, the development of endothelial dysfunction, and increased vascular remodeling. We will extend our investigations into a new metabolic pathway—proline biosynthesis and collagen deposition—in this competitive renewal. This will significantly boost the impact on three levels: first, mechanistically, the proline- collagen axis is receiving renewed interest in the PVD field, but little is known of its role in the endothelium; second, functionally, collagen is a critical regulator of cell proliferation, survival, and angiogenesis; and third, pathologically, changes in collagen alter the mechanical properties of the vessel leading to increased stiffness. Proximal pulmonary artery stiffness is increasingly recognized as an early marker of advancing PVD. Overall, this PPG will continue to focus on increasing our understanding of i) the transcription factors that drive the metabolic rewiring of pulmonary endothelium, ii) post-translational modifications (PTMs) that influence metabolic reprogramming, iii) interactions between mitochondrial network dynamics, metabolism, and cellular survival; iv) how these pathways interact to disrupt hsp90-mediated NO signaling; and v) novel therapeutic strategies for treating CHD with increased PBF. These represent the thematic underpinning of this PPG. Project 1 will investigate the paradigm-shifting hypothesis that the mechanically regulated transcription factor, SOX18, metabolically rewires the endothelium to stimulate proline biosynthesis, leading to collagen deposition and increased vascular stiffness. Project #2 will continue to build on ongoing studies investigating the role of mitochondrially localized pp60Src and PTM-mediated regulation of cellular energetics. Project #3 will continue investigating the role of disrupted mitochondrial network dynamics in developing PVD, focusing on persistent MFN2 loss in a metabolic reprogramming favoring glutamine-proline metabolism. Each project, along with the supporting scientific Cores, will focus on integrated and synergistic investigations to continue to increase our understanding of how the metabolic rewiring of the pulmonary endothelium leads to the hyperproliferative, anti- apoptotic angiogenic EC phenotype, the loss of NO signaling, endothelial dysfunction, and vascular remodeling.


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 = $2,342,524 )
2025	2025	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Lung Diseases Research	000	7	8/28/2025	COMPETING CONTINUATION	$2,342,524
														Subtotal = $2,342,524

Issue Date FY: 2024 ( Subtotal = $2,308,269 )
2024	2024	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Lung Diseases Research	000	6	8/17/2024	NON-COMPETING CONTINUATION	$2,308,269
														Subtotal = $2,308,269

Issue Date FY: 2023 ( Subtotal = $2,379,184 )
2023	2023	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Lung Diseases Research	000	5	9/6/2023	NON-COMPETING CONTINUATION	$2,379,184
														Subtotal = $2,379,184

Issue Date FY: 2022 ( Subtotal = $2,402,459 )
2022	2022	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Lung Diseases Research	005	4	9/16/2022	NON-COMPETING CONTINUATION	$2,402,459
2022	2021	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Lung Diseases Research	001	3	11/25/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$2,366,426
2022	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Lung Diseases Research	000	2	11/18/2021	NON-COMPETING CONTINUATION	-$2,366,426
2022	2021	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Lung Diseases Research	003	3	3/11/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$948,384
2022	2021	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Lung Diseases Research	004	3	9/10/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Lung Diseases Research	002	1	3/11/2022	NEW	-$948,384
														Subtotal = $2,402,459

Issue Date FY: 2021 ( Subtotal = $2,366,426 )
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Lung Diseases Research	000	2	8/11/2021	NON-COMPETING CONTINUATION	$2,366,426
														Subtotal = $2,366,426

Issue Date FY: 2020 ( Subtotal = $2,418,405 )
2020	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Lung Diseases Research	001	1	9/18/2020	NEW	$0
2020	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Lung Diseases Research	000	1	8/10/2020	NEW	$2,418,405
														Subtotal = $2,418,405

Grand Total All Awards = $14,217,267

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METABOLIC REPROGRAMMING AND PULMONARY VASCULAR DISEASE ASSOCIATED WITH CONGENITAL HEART DISEASE RESULTING IN INCREASED PULMONARY BLOOD FLOW

Award Number: P01HL146369

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/10/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2030

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