This application seeks continued funding for our multidisciplinary Burn Trauma Center which began in 1974. The Center has continued to evolve to keep pace with the exciting new knowledge in biology and the state-of-the- art methods for conduct of clinical investigations and mechanistic studies in model systems. The Center's research addresses the underlying basis for metabolic events produced by life-threatening hypermetabolism and organ failure of severe burn injury. The unifying hypothesis is that burn injury uniquely changes the homeostasis of nitrogen and major energy-yielding substrate metabolism and profoundly reintegrates inter-organ cooperatively in nitrogen and energy economy. The net effect is a nitrogen catabolic state which compromises wound healing and recovery and currently, this state is refractory to treatment. This reintegration leads to a redistribution of amino acid, protein, and substrate metabolism among the wounded tissues and major organs by reordering carbon and nitrogen flow within and among body regions. To test the foregoing hypothesis, investigations are conducted in healthy volunteers and patients at the whole body level using non-invasive state-of-the-art clinical investigation tools. Human studies are necessary because the metabolic status of the burned patient represents more than a sum of the elements of metabolism studied in isolation. Mechanistic studies are also needed if rational and more effective metabolically designed substrate (nutritional) and pharmacological interventions are to be developed to improve patient care. Therefore, the defining feature of this Center is an exciting, integrated mixture of human and animal studies, in vivo and in vitro, observational, interventional, basic, and more applied studies with a major focus on interrelated aspects of specific amino acids, glucose, and fatty acid metabolism and the multiple signals involved. Thus, four projects are proposed: addressing (1) energy and nitrogen metabolism; (2) tissue-specific contributions to the altered metabolic state; (3) molecular mechanisms of burn-induced insulin resistance; and (4) molecular basis of hepatic hypermetabolism in burns. These synergistic studies will interact within and be supported by the Core facilities which provide technical, professional, and analytical services. These facilities include: (1) Clinical studies, (2) Animal studies, (3) Mass spectrometry, (4) Nuclear magnetic resonance spectroscopy, (5) Cyclotron and radiochemistry, and PET camera, (6) Computational and statistical consultation, and (7) Biochemical synthesis and image analysis.
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