DESCRIPTION (provided by applicant): This proposal describes a five-year career development program to prepare the candidate, Dr. Michael Coronado, for a career as an independent scientist. This program will expand Dr. Coronado's scientific background in cardiovascular research by providing technical training and expertise in mitochondrial and myocardial biology. Dr. Coronado's mentor is Dr. Daniel Bernstein, the Salter Endowed Professor of Pediatrics (Cardiology) at Stanford University. Dr. Bernstein is an expert in myocardial G protein coupled receptor signaling, director of Stanford's Myocardial Biology T32 Training Grant, former Chief of Pediatric Cardiology, and has over two decades of experience mentoring young scientists. The K99 phase of the grant will provide the necessary intellectual background and training to foster Dr. Coronado's successful transition from a mentored postdoctoral fellow into an independent scientist. This will be accomplished by developing four essential characteristics of an independent scientist including: (1) unique technical skills, methodologies and tools, (2) the ability to conceptualize scientific questions and generate hypothesize-driven experiments, (3) communication and collaborative skills and (4) mentorship and laboratory management skills. These characteristics will be developed through performing the novel research described in this proposal, receiving mentorship from an expert advisory committee, participating in courses and workshops and mentorship of students and postdocs. Dr. Coronado's long-term scientific career goal is to establish a research program to further investigate the mechanisms by which mitochondrial function and dynamics are regulated in cardiovascular health and disease. Preliminary studies by Dr. Coronado show a close connection between β-adrenergic receptors (ARs) and mitochondria, both of which play a unique dual role in regulating both cardiac energetics and cell death. Mitochondria are the principal source of energy for cardiac contraction, and β-ARs, the major regulators of cardiac energy demand. During exercise, mitochondria must quickly respond to increased energy demands. Since β-ARs are responsible for regulating the rate and strength of contraction, it is logical that they also regulate the signaling pathways that enable the cell to meet acute energetic demands. Mitochondria are also key regulators of apoptosis, a consequence of excessive β-AR stimulation, suggesting another connection between β-ARs and mitochondrial dynamics. Dr. Coronado's preliminary studies show that activation of the β1- AR both pharmacologically (in vitro) and with exercise (in vivo) results in fragmented mitochondria with enhanced respiration. A key observation is that pharmacological inhibition of Drp1-mediated mitochondrial fragmentation results in significantly decreased exercise capacity and an early shift towards anaerobic pathways of ATP generation. The current paradigm considers fragme...