Effect of cysteine on glutathione production in critically ill neonates

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DESCRIPTION (provided by applicant): The candidate is a pediatric surgeon and Assistant Professor of Surgery at the David Geffen School of Medicine at UCLA, whose long-term goal is to become an independent clinician-scientist with research that will make a significant impact on diminishing the illnesses endured by neonates. Through the guidance from experienced scientific investigators as mentors and an extensive network of educational, research, and clinical facilities available at UCLA, the purpose of this proposal is to foster the candidate's academic career development over a five-year period. The proposal involves acquiring the training to become an independent clinician-scientist while investigating the effect of cysteine on the production of the antioxidant glutathione and its impact on oxidative tissue injury in critically ill neonates. Low levels of cysteine and glutathione have been demonstrated in critically ill neonates who have a high incidence of disease associated with oxidative-injury, such as chronic lung disease and necrotizing enterocolitis. Cysteine is the rate limiting substrate for the synthesis of glutathione, but it is not readily synthesized by nor routinely given to critically ill, parenterally fed neonates. The candidate hypothesizes that critically ill neonates administered cysteine supplementation with their routine parenteral nutrition will have a higher rate of synthesis and stored levels of glutathione that will subsequently result in a diminished cytokine inflammatory response, less oxidative tissue injury, and a decrease in the severity of oxidative-injury associated diseases compared to similar neonates without cysteine supplementation. To test this hypothesis, a randomized, prospective, double-blinded, clinical trial of cysteine supplementation to critically ill neonates fed isonitrogenous parenteral nutrition is proposed with the following specific aims: (1) to measure total concentrations of erythrocyte glutathione, redox ratios of erythrocyte glutathione, and the in vivo synthetic rates of erythrocyte glutathione utilizing a novel non-radioactive, stable isotope tracer technique with [13C]-glycine, (2) to measure plasma interleukin-6, tumor necrosis factor-a, and malondialdehyde concentrations as determinants of inflammatory response severity and degree of oxidative tissue injury, and (3) to measure the duration of mechanical ventilation, supplemental oxygen, and hospitalization as primary clinical outcomes of disease severity. The data obtained should provide insight into the previously uncharacterized in vivo kinetics of glutathione synthesis and the pathogenesis of oxidative tissue injury in critically ill neonates, as well as suggesting potential therapeutic approaches to improve antioxidant defense, such as cysteine supplementation. The result of this investigation could ultimately change the standard nutritional and treatment practices for critically ill neonates in order to improve the outcome for these extremely fragile patients.