# Mechanisms of Large Animal RV Dysfunction

> **NIH NIH F31** · UNIVERSITY OF MINNESOTA · 2024 · $35,323

## Abstract

Project Summary/Abstract
The goals of this proposal are to further train Jenna Mendelson as a scientist conducting cardiovascular basic
science research to combat cardiovascular disease and to advance the understanding of the mechanisms of
right ventricular dysfunction (RVD) in a large animal model. RVD is a significant risk factor for death in
cardiovascular disease. Yet, there are currently no therapies that directly target the right ventricle. Although
small animal studies reveal important mechanisms, these findings are difficult to translate to humans. Porcine
models may be a better bridge to humans because the anatomical size, structure, and physiology of porcine
hearts are more similar to humans. Furthermore, we recently showed that in RVD, pigs have a metabolic
molecular signature that more closely recapitulates human disease compared to rodents. Mitochondria are
energy producing organelles that maintain cellular metabolism. Patients and animal models of RVD have
mitochondrial metabolic dysfunction and reduced fatty acid metabolism, leading to insufficient ATP to meet
cardiac energy demands. Glycoprotein 130 (GP130) is the ubiquitously expressed master membrane receptor
for interleukin-6 superfamily of inflammatory cytokines. Downstream GP130 activation alters mitochondrial
function, and in a rat model of pulmonary hypertension, we showed that inhibition of GP130 with the small
molecule SC144 improved mitochondrial morphology, increased fatty acid oxidation, and improved RV
function. Therefore, this research project will investigate the hypothesis that in a large animal model of RV
pressure overload induced RVD, GP130 antagonism with SC144 will improve RV function by improving
mitochondrial fatty acid metabolism. Aim 1 investigates the hypothesis that GP130 antagonism will improve RV
function in a porcine model of pulmonary artery banding. Aim 2 will determine if GP130 antagonism with
SC144 improves fatty acid metabolism. In both aims, we will utilize in-depth physiological assessments
(cardiac MRI and pressure-volume loop analysis), super resolution confocal microscopy, electron microscopy
analysis, proteomics, metabolomics, lipidomics, and molecular biology approaches to determine the effects of
GP130 antagonism with SC144 on RV function and mitochondrial metabolic function. This project has the
potential to link mitochondrial dysfunction to cardiac MRI and hemodynamic measurements of RV function in
large animals, and identify GP130 signaling as a pharmacological target for RVD. Furthermore, the training of
Ms. Mendelson through this translational proposal will advance the mission of the NIH by helping support the
training of a scientist who will conduct clinically relevant research.

## Key facts

- **NIH application ID:** 10995750
- **Project number:** 1F31HL170585-01A1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Jenna Blair Mendelson
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $35,323
- **Award type:** 1
- **Project period:** 2024-09-30 → 2026-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10995750

## Citation

> US National Institutes of Health, RePORTER application 10995750, Mechanisms of Large Animal RV Dysfunction (1F31HL170585-01A1). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10995750. Licensed CC0.

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