PROJECT SUMMARY Heart failure (HF) is a cardiovascular disease (CVD) of major significance, as half of HF patients die within five years of diagnosis. HF often develops following cardiac injury, when the heart is unable to pump effectively and compensates by enlarging (hypertrophy) and changing its structure (remodeling). Initially these alterations maintain normal cardiac output, but the heart cannot sustain the increased energetic demand and eventually its function decompensates. Therefore, identifying novel therapeutic targets for HF is of utmost importance. Our lab has studied G protein-coupled receptors (GPCRs) for over two decades, with a focus on G protein- coupled receptor kinases (GRKs), which phosphorylate and desensitize GPCRs. Two GRKs in particular, GRK2 and GRK5, are known to be highly upregulated during HF, and this proposal focuses on novel, non- GPCR roles for GRK2 in HF. Recently, (mtGRK2) output, to mitochondrial metabolism. it has been shown that cytosolic GRK2 accumulates in mitochondria following cardiac injury or stress, and this event is associated with negative effects on energy substrate utilization, and ell death. However, the molecular mechanisms by which mtGRK2 contributes HF are unknown. Preliminary data presented in this proposal confirm that GRK2 interacts with important proteins, particularly components Our Central Hypothesis is c of the electron transport chain (ETC) and fatty acid that mtGRK2 plays a critical role in regulating cellular bioenergetics following cardiac stress. As such, the Specific Aims proposed are to (Aim 1) identify the nature of mtGRK2's interactions with components of the ETC, and the mechanism of its negative regulation of cellular bioenergetics; and (Aim 2) determine the mtGRK2-driven metabolic changes seen in chronic HF which develops following ischemic injury in an animal model of HF, and whether inhibition of mtGRK2 can improve outcomes by rescuing its negative effects on mitochondrial metabolism. The detailed research strategy combined with the projected training plan is meant to develop the student into a successful, independent scientist. All required Ph.D. coursework and requirements for candidacy have been completed by the trainee, who will continue to receive training in scientific rigor, biomedical ethics, and laboratory safety. Additionally, the training plan includes an emphasis on career development activities such as publications, talks and seminars, and attendance at scientific meetings. This proposal further develops the trainee's skills in molecular biology, biology, pharmacology and cardiovascular physiology; therefore, it is well-suited to strengthening areas which will be required for a future Principal Investigator in the field of cardiovascular pharmacology.