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.