This proposal is designed to broaden Dr. Levy's experience and hone basic science skills with direct mentorship. Through this process, the aim is for the junior investigator to become more facile with laboratory skills, scientific writing, research design, and experimental methodology. Both the Children's Hospital of Philadelphia and the University of Pennsylvania are intellectually rich environments with a wide variety of resources and personnel with tremendous expertise and diversity. Multi-disciplinary collaboration occurs daily and the opportunities are almost limitless. Sepsis, the systemic inflammatory response syndrome (SIRS), and multiple organ dysfunction syndrome (MODS) are the most common causes of mortality in critically ill surgical patients. Cardiac dysfunction occurs commonly in septic patients. One hallmark of sepsis is cytopathic hypoxia, where cells are unable to use molecular oxygen for energy production. Such a defect could underlie sepsis-associated organ dysfunction. Initial studies demonstrate that myocardial cytochrome c oxidase, the terminal oxidase of the electron transport chain, is competitively inhibited early in sepsis, progressing to irreversible inhibition later during the hypodynamic phase of sepsis. This specific defect in oxidative phosphorylation may lead to cytopathic hypoxia. In this proposal, we aim to precisely characterize sepsis-associated cardiac dysfunction with precise measurement of intracardiac volumes using MRI technology, evaluate one potential cause of irreversible cytochrome oxidase inhibition;failed mitochondrial transcription, and evaluate one potential effect;initiation of the mitochondrial apoptotic pathway. The long term goal of this proposal is to identify a specific area that may be amenable to therapeutic intervention. The research design will lay ground work allowing Dr. Levy to mature into a competent, independent researcher. Along with preliminary data, this proposal will allow the junior investigator to develop a research career focused on mitochondrial dysfunction, cytopathic hypoxia, and sepsis-associated myocardial depression.
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