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Nanoparticle-mediated metabolic reprogramming of endothelial cells in pulmonary arterial hypertension (PAH)

Award Number: F31HL184847
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2026
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Nanoparticle-mediated metabolic reprogramming of endothelial cells in pulmonary arterial hypertension (PAH) - Project Summary/Abstract Pulmonary arterial hypertension (PAH) is a progressive disease marked by increased pulmonary vascular resistance, leading to right ventricular failure and death. In PAH, microvascular endothelial cells (MVECs) abnormally proliferate to form plexiform lesions, which occlude the microvasculature. Maladaptive microvascular endothelial cell (MVEC) proliferation in PAH is thought to be driven, in part, by pathogenic metabolic shifts. Increased fatty acid oxidation (FAO) and ketogenesis (i.e. production of the ketone body beta-hydroxybutyrate; BOHB) have been recently observed in PAH MVECs. BOHB production is regulated in the mitochondria by beta- hydroxybutyrate dehydrogenase (Bdh1), an enzyme whose activity is also increased in PAH MVECs. Furthermore, our preliminary data suggests that inhibiting BOHB production is sufficient to decrease PAH MVEC proliferation. These data suggest that BOHB production may represent a druggable target in PAH, but the mechanisms by which these metabolic shifts inform disease progression remain unstudied, largely because of technical limitations that complicate perturbing metabolism on an organ-specific and cell-specific basis in vivo. As nanoparticle-mediated strategies can enable the direct modulation of specific metabolites without globally disrupting metabolic pathways, we seek to develop a lipid nanoparticle (LNP) optimized for pulmonary MVECs to modulate metabolites of interest, particularly employing plasmid DNA to upregulate Bdh1 and siRNA to silence Bdh1. Employing a multi-step screening approach, we can identify optimized LNP formulations capable of delivering a range of nucleic acid payloads to the pulmonary vascular bed, which can support the investigation of other molecular targets in this setting and be applied to other pulmonary disease areas. The aims in this proposal will allow us to investigate local metabolic shifts, specifically in Bdh1-regulated BOHB production, and ascribe a molecular and pathophysiological basis to these observed differences in experimental models of PAH. The highly interdisciplinary nature of this proposal integrates iterative engineering principles to design and identify optimal delivery vehicles for this model as well as employs advanced techniques in assessing MVEC molecular changes and vascular remodeling in PAH. If successful, we hope this proposal can elucidate key mechanisms of PAH pathogenesis and lay a foundation to explore the therapeutic utility of decreasing BOHB production.


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: 2026 ( Subtotal = $50,114 )
2026	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Lung Diseases Research	000	1	4/13/2026	NEW	$50,114
														Subtotal = $50,114

Grand Total All Awards = $50,114

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Nanoparticle-mediated metabolic reprogramming of endothelial cells in pulmonary arterial hypertension (PAH)

Award Number: F31HL184847

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2026

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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