Nanoparticle-mediated metabolic reprogramming of endothelial cells in pulmonary arterial hypertension (PAH)
Active Project Grant Awarded Last action
- Award ID
- F31HL184847
- Recipient
-
The Johns Hopkins University UEI FTMTDMBR29C7
- Awarding agency
-
National Heart Lung and Blood Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $50,114
Award facts
- Assistance listing
- 93.837 Cardiovascular Diseases Research
- Completion date 0% complete
- Place of performance
- Baltimore, MD 21205, USA
Award details come from USAspending.gov.
Description
- 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.
Quick answers
Who received award F31HL184847?
F31HL184847 was awarded to The Johns Hopkins University by National Heart Lung and Blood Institute (National Institutes of Health) on December 1, 2026.
How much is award F31HL184847 worth?
$50,114 has been obligated on F31HL184847.
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