Increased loss of body protein (nitrogen) particularly from skeletal muscles, with the development of a profound catabolic state with extensive alteration of the amino acid, glucose and energy economy of the individual are characteristics of a major burn injury. These compromise cell function, organ function, host defense and, increase morbidity. They have proven difficult to reverse and contemporary nutritional thera- peutic modalities have been ineffective. Through application of stable nuclide tracer techniques, the specific aims of this project are: (a) to reduce muscle protein wasting in burn injury through understanding of muscle, gut, liver amino acid substrate interactions including investigation of carbon skeletal exchanges, nitrogen trafficking and urea production [Studies include the characterization of whole body and limb amino acid kinetics in burn patients and detailed studies of interorgan (gut/liver, muscle, kidney) amino acid metabolism in a chronically catheterized animal model]; (b) to define arginine, ornithine, citrulline kinetics with particular reference to nitric oxide production during uncomplicated and complicated burn illness; (c) to characterize the simultaneous changes in amino acid fluxes across muscle gut and liver, including a quantitation of fluxes of Krebs cycle intermediates and rates of carbon entry into the cycle, using animal models and a combination of NMR, mass-spectrometry and the cylotron to identify labeling of derivatives of glutamate and lactate; and (d) to continue an exploration of the role played by glutamate, cysteine, tyrosine, arginine and proline as """"""""conditionally essential"""""""" amino acids, including estimations of their rates of de novo synthesis with the potential benefit for the amino acid economy emerging from the administration of cystine and tyrosine etc. in dipeptide form.
These aims will be accomplished via a series of interrelated metabolic investigations in healthy adults and burn patients, supplemented with studies using experimental animal models. These studies will exploit classic mass spectrometric techniques supplemented by innovative combined NMR and cyclotron techniques adding considerable specificity and sensitivity. New and exciting information concerning the in vivo interorgan metabolic regulation and interorgan utilization of specific amino acids in human subjects is expected, allowing formulation and evaluation of nutritional/therapeutic modalities designed to reduce morbidity and mortality.
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