This proposal describes a five-year career development and training plan for Dr. Marcello Panagia, a physician-scientist, who at the time of the award will have completed training in Cardiovascular Medicine and Advanced Cardiac Imaging (MR/CT/PET) at Massachusetts General Hospital (MGH). Under the mentorship of Dr. David Sosnovik and Dr. Robert Gerszten, Dr. Panagia is now embarking on a cutting-edge research plan that combines his background in cardiac energy metabolism with advanced imaging technologies. His career development plan, that leverages the extensive resources offered by MGH, brings together a robust team of investigators with expertise in molecular imaging, metabolomics, signal transduction and magnetic resonance imaging. During the period of funding, Dr. Panagia will have faculty positions in the Cardiology and Radiology Divisions at MGH as well as a faculty appointment at Harvard Medical School. His ultimate goal is to become an independent investigator studying energy metabolism with a sophisticated tool-kit of imaging technologies. Receipt of this award will allow Dr. Panagia to obtain additional training in optical imaging, magnetic resonance imaging and spectroscopy, metabolomics, biostatistics, research design and ethics, and will facilitate his transition to research independence. In addition to providing a mechanism for further training, the award will allow Dr. Panagia to continue studies in the dysregulation of energy metabolism in heart failure. Heart failure is a leading cause of morbidity and mortality in the United States and the dysregulation of energy metabolism is a fundamental feature of its pathogenesis. However, the capacity to adequately study the processes involved in energy metabolism could be significantly improved. Although valuable, current techniques are limited by their complexity, relatively low throughput, and inability to image multiple processes at the same time. Dr. Panagia hypothesizes that a novel optical approach can permit the simultaneous imaging of multiple metabolic and energetic pathways in the heart and peripheral tissues and provide important insights into heart failure pathogenesis. Dr. Panagia has obtained preliminary results that show the feasibility of this approach in a coronary ligation model of heart failure. He has shown that Cerenkov luminescence using 18F- fluorodeoxyglucose in this model clearly differentiates viable myocardium from scar and that simultaneous imaging with mitochondrial-targeted probes provides valuable time-coherent and spatially coherent information. This optical approach will be enhanced by the use of non-invasive measures of metabolic activity, such as peripheral tissue oxygen consumption by magnetic resonance imaging, as well as high-throughput screening of blood and tissue metabolites (metabolomics). Dr. Panagia proposes to extend the investigation to include multiple models of heart failure of different etiologies and to examine, in more detail, the energetic features that underlie the transition from compensated to decompensated heart failure. In summary, by bringing together cutting edge technology and a well-rounded team of experts in the context of a well-defined research plan and mentorship structure, Dr. Panagia will be able to synergistically merge the fields of advanced imaging and energy metabolism to elucidate novel mechanisms that underlie cardiac pathophysiology and elaborate the skills essential for him to become an independent investigator.