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Metabolic mechanisms underlying bronchopulmonary dysplasia-associated pulmonary hypertension

Award Number: R01HL166327
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Metabolic mechanisms underlying bronchopulmonary dysplasia-associated pulmonary hypertension - SUMMARY Bronchopulmonary dysplasia (BPD) is a chronic lung disease in premature infants, caused by mechanical ventilation and hyperoxia amongst other factors. Thirty percent of infants with moderate to severe BPD develop pulmonary hypertension (PH), characterized by pulmonary vascular remodeling. There are no curative therapies for this disease. Current management is limited to relieving symptoms using pulmonary vasodilators, and minimizing further lung vascular and alveolar insults. My long-term goal is to develop novel targeted therapies to prevent and/or treat BPD associated pulmonary hypertension (BPD-PH). Pulmonary vascular remodeling is characterized by increased smooth muscle cell-specific markers. This results from proliferation and migration of vascular smooth muscle cells, or transdifferentiation from endothelial cells (ECs) to smooth muscle cells (i.e., endothelial-mesenchymal transition, EndoMT). We and others have shown that hyperoxia to newborn mice and mechanical ventilation in preterm lambs cause pulmonary vascular remodeling resulting in PH. This is associated with increased EndoMT, as shown in our recent publication and in preliminary data. We preliminarily show that EndoMT is also observed in the lung of premature infants requiring mechanical ventilation, suggesting that this may be causative in pulmonary vascular remodeling and PH. In mice, we have reported that neonatal hyperoxia causes a persistent reduction of endothelial carnitine palmitoyltransferase 1a (Cpt1a), the rate-limiting enzyme of the carnitine shuttle system responsible for transporting long-chain fatty acids into mitochondria for β-oxidation during fatty acid oxidation. Our preliminary data show that lung Cpt1a gene expression is also reduced in mechanically ventilated preterm lambs and premature human infants. Additionally, endothelial deletion of Cpt1a increased EndoMT and pulmonary vascular remodeling in neonatal mice after exposure to hyperoxia. Furthermore, pharmacological upregulation of Cpt1a attenuated hyperoxia-induced EndoMT in cultured lung ECs. Whether neonatal hyperoxia and mechanical ventilation reduce endothelial Cpt1a, leading to PH is yet to be determined. The central hypothesis is that neonatal hyperoxia and mechanical ventilation cause EndoMT by downregulating endothelial Cpt1a, thereby resulting in pulmonary vascular remodeling and PH. We will test this hypothesis in three Specific Aims. Aim 1 will determine the molecular mechanisms by which Cpt1a regulates hyperoxia-induced EndoMT. In Aim 2, we will define the role of endothelial Cpt1a in neonatal hyperoxia-induced PH and EndoMT. In Aim 3, we will evaluate endothelial Cpt1a and EndoMT as therapeutic targets for BPD-PH using both lamb and mouse models. The combination of clinically relevant lamb and mouse models with our newly generated EC-specific Cpt1a KO mice and newly developed nanoparticle delivery system provides an innovative approach to uncover the mechanisms by which Cpt1a reduction mediates EndoMT and their significant roles in BPD-PH. This contribution is significant because it is likely to result in new therapies specifically targeting endothelial Cpt1a or EndoMT in neonates to prevent or cure BPD-PH.


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 = $560,893 )
2025	2025	OCEAN STATE RESEARCH INSTITUTE INC	830 CHALKSTONE AVE	NORTH PROVIDENCE	RI	02908	PROVIDENCE	USA	Lung Diseases Research	002	3	4/9/2025	NON-COMPETING CONTINUATION	$504,803
2025	2025	OCEAN STATE RESEARCH INSTITUTE INC	830 CHALKSTONE AVE	NORTH PROVIDENCE	RI	02908	PROVIDENCE	USA	Lung Diseases Research	003	3	6/26/2025	NON-COMPETING CONTINUATION	$56,090
2025	2024	OCEAN STATE RESEARCH INSTITUTE INC	830 CHALKSTONE AVE	NORTH PROVIDENCE	RI	02908	PROVIDENCE	USA	Lung Diseases Research	001	2	3/18/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$407,405
2025	2023	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Lung Diseases Research	000	1	3/18/2025	NEW	-$407,405
														Subtotal = $560,893

Issue Date FY: 2024 ( Subtotal = $556,147 )
2024	2024	OCEAN STATE RESEARCH INSTITUTE INC	830 CHALKSTONE AVE	NORTH PROVIDENCE	RI	02908	PROVIDENCE	USA	Lung Diseases Research	001	2	5/20/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$556,147
2024	2023	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Lung Diseases Research	000	1	5/19/2024	NEW	$0
														Subtotal = $556,147

Issue Date FY: 2023 ( Subtotal = $657,427 )
2023	2023	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Lung Diseases Research	000	1	6/15/2023	NEW	$657,427
2023	2023	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Lung Diseases Research	001	1	8/21/2023	NEW	$0
														Subtotal = $657,427

Grand Total All Awards = $1,774,467

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Metabolic mechanisms underlying bronchopulmonary dysplasia-associated pulmonary hypertension

Award Number: R01HL166327

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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