Patients with severe illnesses of diverse etiologies, including trauma, infections, burn injuries, major surgery, and certain cancers, frequently develop a catabolic response that contributes to disease morbidity and complications, delays recovery, and may affect final disease outcome. Intensive nutrition support has significant benefit in catabolic patients, but current methods of nutrition support often are not effective in reversing the catabolic state. In these patients, resistance to the actions of anabolic hormones, including insulin, growth hormone, and possibly the growth factor IGF-I, appears to be a significant contributing factor to the catabolic response. In considering the causes of anabolic hormone resistance, as well as the causes of the overall catabolic response, current evidence suggests important roles for both nutrient depletion and cytokines, such as tumor necrosis factor alpha (TNFalpha). Recent data indicate that protein tyrosine phosphorylation reactions are involved in the cellular actions of insulin, growth hormone, and IGF-I, and that TNFalpha inhibits hormone-stimulated tyrosine phosphorylation. The objectives of this project are to investigate the role of altered tyrosine phosphorylation and other signaling reactions in catabolic states by studying: [1] the molecular mechanisms through which nutrient depletion causes or contributes to anabolic hormone resistance, [2] the molecular basis for TNFalpha-induced anabolic hormone resistance, [3] the interrelationships between the effects of nutrient depletion and the actions of TNFalpha, and [4] a new approach to treating the catabolic response by augmenting tyrosine phosphorylation-related signaling. Novel experimental methods developed in the Principal Investigator's laboratory for the investigation of molecular signaling events in the tissues of intact laboratory rats, using specific antibodies and cDNA probes to isolate and quantify hormone pathway intermediates, will be applied to studies on the effects of nutrient deprivation and TNFalpha administration on anabolic hormone action. This experimental approach will be made possible through the collaborative efforts of the Principal Investigator, with his expertise in nutritional molecular biology and biochemistry, and two Co- investigators, with expertise in nutrition, cytokines, and specialized methods required for intact animal studies. The work will investigate fundamental molecular mechanisms of the catabolic response in pathophysiologically relevant experimental models with the ultimate goal of developing new approaches to the use of nutritional, hormonal, and pharmacological interventions in the treatment of catabolic patients.
Showing the most recent 10 out of 15 publications
