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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Clinical Investigator Award (CIA) (K08)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Dunsmore, Sarah
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Children's Research Institute
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Cheng, Ying; Thomas, Adia; Mardini, Feras et al. (2012) Neurodevelopmental consequences of sub-clinical carbon monoxide exposure in newborn mice. PLoS One 7:e32029
Groening, Portia; Huang, Zhishan; La Gamma, Edmund Frances et al. (2011) Glutamine restores myocardial cytochrome C oxidase activity and improves cardiac function during experimental sepsis. JPEN J Parenter Enteral Nutr 35:249-54
Levy, Richard J (2011) Clinical effects and lethal and forensic aspects of propofol. J Forensic Sci 56 Suppl 1:S142-7
Levy, Richard J; Nasr, Viviane G; Rivera, Ozzie et al. (2010) Detection of carbon monoxide during routine anesthetics in infants and children. Anesth Analg 110:747-53
Verma, Richa; Huang, Zhishan; Deutschman, Clifford S et al. (2009) Caffeine restores myocardial cytochrome oxidase activity and improves cardiac function during sepsis. Crit Care Med 37:1397-402
Piel, David A; Deutschman, Clifford S; Levy, Richard J (2008) Exogenous cytochrome C restores myocardial cytochrome oxidase activity into the late phase of sepsis. Shock 29:612-6
Levy, Richard J; Deutschman, Clifford S (2007) Deficient mitochondrial biogenesis in critical illness: cause, effect, or epiphenomenon? Crit Care 11:158
Iheagwara, Kelechi N; Thom, Stephen R; Deutschman, Clifford S et al. (2007) Myocardial cytochrome oxidase activity is decreased following carbon monoxide exposure. Biochim Biophys Acta 1772:1112-6
Levy, Richard J; Deutschman, Clifford S (2007) Cytochrome c oxidase dysfunction in sepsis. Crit Care Med 35:S468-75
Levy, Richard J (2007) Mitochondrial dysfunction, bioenergetic impairment, and metabolic down-regulation in sepsis. Shock 28:24-8

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