The candidate is a pediatric cardiologist with a commitment to career in academic medicine. The proposed research will focus on mechanisms of injury caused by ischemia and reperfusion in the immature heart,a topic of relevance in pediatric cardiology. Our approach is to define changes in two interrelated areas of metabolism, energy metabolism and transmembrane cation exchange, during development in the rabbit heart and, with this information, to determine susceptibility to ischemic and reperfusion injuries. In addition to studying hearts undergoing normal development, we will develop new models of chronic hypoxia and hypertrophy caused by volume and pressure overload. This strategy will allow study of the immature myocardium under conditions physiologically relevant to congenital heart disease. Using isolated, perfused rabbit hearts, both traditional biochemical techniques and new NMR spectroscopy tools will be employed to define changes in 1) key enzymes involved in ATP synthesis (mitochondrial and glycolytic enzymes), energy transport (creatine kinase), and utilization (myosin); 2) metabolites including ATP, creatine phosphate, glycogen, and lactate and 3) cations, H+, Na+, K+ and Ca++, during normal and abnormal development and during ischemia and reperfusion. We will measure the glycolytic rate (3H20 production from 2-(3H) glucose), the rate of lactate production (lH NMR), the rate of oxidative phosphorylation (oxygen consumption) and the creatine kinase reaction velocity (saturation transfer 31P NMR). ATP, creatine phosphate (CrP), and inorganic phosphate contents and pH will be measured using 31P NMR spectroscopy. Intra- and extracellular concentrations of Na+, K+ and Ca++ will be measured using new NMR techniques developed in our laboratory. All of these measurements permit simultaneous assessment of cardiac performance. The Harvard Medical School and Children's Hospital provide the clinical and basic science expertise and facilities necessary for achieving the goals of the Clinical Investigator Award.
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