PROJECT SUMMARY Although the ubiquity of metabolic problems in pulmonary hypertension (PH) has been known for more than a decade, a wealth of new details on the nature of this problem presents the opportunity for intervention. A combination of experimental work in cells and animals and early trials in humans, suggests that these metabolic problems are part of the causation for PH, and that inactivation of the mitochondrial lysine deacetylase SIRT3 is a central node in regulating the metabolic defects. A vicious cycle exists in which a triggering event or mutation increases reactive oxygen species (ROS), which produces reactive lipids, which adduct and inactivate SIRT3, causing metabolic changes that result in further increased ROS. Here, we break this cycle using 2-HOBA, a small molecule which can effectively soak up reactive lipids in vivo and our preliminary studies show that 2-HOBA is a safe compound and in IND enabling animal toxicity and human safety trials and shows great promise in treating the core molecular defects in PH. Our preliminary data and Phase I studies demonstrate not only clear positive impact on reducing pulmonary vascular resistances in Group I and II PH, and both cytokine and molecular biomarkers of disease, but also indicated the potential for a substantial positive effect on heart function under load stress. In this Phase II project, we will establish the remaining data needed to proceed to commercialization through the following aims: 1) we will test the safety and molecular efficiency of 2-HOBA in PH patients in a small open label mechanistic pilot trial with of two weeks of 2-HOBA exposure; 2) we will demonstrate efficacy of 2HOBA in improving function of the right ventricle under stress in a well-established sheep model; and 3) we will test effectiveness of 2-HOBA alone and in the context of standard-of-care in mouse models and large animals. 2-HOBA is an entirely new approach to solving a molecular problem that several existing clinical trials and case reports have tried to resolve, but so far with limited success. The specific mechanism of action of 2-HOBA should allow it to succeed where other interventions have failed.