PROJECT SUMMARY Heart failure in the presence of diabetes is common, expensive, and growing in significance, with some estimates suggesting that diabetic cardiomyopathy is present in up to 60% of patients with diabetes. While typically thought of as a disease of the left ventricle, right ventricular (RV) remodeling also occurs and contributes to disease pathogenesis. In multiple clinical conditions, RV dysfunction is the strongest predictor of mortality, clearly highlighting the significance of maintaining RV function. Despite the strong link between RV function and survival, understanding of the diabetic RV is limited and thus there is a critical need to identify mechanisms of RV-specific remodeling in the diabetic heart. In the setting of diabetes, altered myocardial substrate metabolism causes oxidative stress, which together contribute to LV dysfunction. However, despite strong rationale for these mechanisms in the diabetic LV, they are unstudied in the RV. The purpose of this Katz Early Stage Investigator proposal is to identify RV-specific mechanisms of diabetic myopathy. To achieve this goal, we propose to 1) determine the mechanism by which fatty acid uptake contributes to RV lipotoxicity and dysfunction, and 2) identify mechanisms of impaired reactive oxygen species signaling in the diabetic RV. Together, we will demonstrate that RV dysfunction is significant in diabetes by a mechanism involving lipotoxicity and oxidative stress. Identifying RV-centric mechanisms of disease is critical to advance our long- term goal of identifying treatments for the failing RV. If RV mechanisms are distinct from those in the LV, then current therapeutic approaches will be limited in improving RV function and patient outcomes. This novel and innovative body of work will lay the groundwork for future larger efforts aimed at understanding the mechanisms of diabetic RV cardiomyopathy and the identification of therapies for this unmet public health need.