Burn injury induces extensive oxidative stress which leads to derangements in the physiology of a variety of tissues. Over the past several years we have conducted extensive genome-wide studies aimed at mapping genes the transcription of which are increased or decreased after burn injury in human subjects over the time course after injury. These studies have revealed changes in transcriptions of hundreds of genes in skeletal muscle and adipose tissue that are key mediators ofthe metabolic alterations associated with burn injury. Base on these findings, we hypothesize that administration of agents that reduce this oxidative stress by scavenging reactive oxygen species (ROS) will aid in normalization of the metabolic alterations induced by burn injury. The tetra peptide SS-31 (D-Arg-Dmt-Lys-Phe-NH2) is an extremely potent mitochondrial targeted ROS scavenger and thus is a particulariy promising candidate molecule for this purpose. In this project we plan to study the effects of SS31 treatment of burn induced alterations in skeletal muscle metabolism at both the genetic and physiological levels. In the first Specific Aim, we plan to develop a chip for studying SS31 induced alterations in gene expression in murine models of burn injury.
In Specific Aim 2 we plan to perform parallel studies ofthe effects of SS31 on physiological alterations induced by burn injury in mice,including: 1. Treatment on plasma glucose and insulin kinetics and insulin sensitivity of skeletal muscle after burn injury. 2. PET studies ofthe effects of SS31 on burn induced alterations in: a. glucose metabolism, b. fatty acid metabolism, c. TCA cycle activity, d. mitochondrial function and d. muscle cell apoptosis associated with injury. 3. Stable isotope studies ofthe effect of SS31 on burn induced alterations in glucose, amino acid and fatty acid metabolism.
In Specific Aim 4, we will extend these investigations of the effect(s) of SS31 on mitochondrial function to higher animals;initially Rhesus monkeys treated with lipopolysaccharide (LPS) and ultimately humans with burn injury. Overall, our studies will provide a firm basis for future clinical trials of SS31 for the treatment of alterations in mitochondrial function produced by burn injury.
These studies will establish the role of SS31 in reducing the oxidative stress by scavening reactive oxygen species (ROS) after burn injury and should provide insights for the design of future clinical trials of this peptide for the treatment of alterations in mitochondrial function produced by burn injury.
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