Burn injury induces a massive state of oxidative stress, which leads to derangements in the physiology of a variety of tissues. Over the past several years, the NIGMS-funded Glue Grant program, Inflammation and the Host Response to Injury has conducted extensive genome-wide studies mapping gene transcriptional regulation (increased or decreased) after burn injury in humans over time. These studies have revealed a genomic storm in the circulating white cells of which thousands of genes were highly regulated in blood, skeletal muscle, skin, and fat and described a transcriptome supporting many of the metabolic alterations associated with burn injury. It is widely believed that the creation of reactive oxygen species (ROS) significantly contributes as a cause for the metabolic alterations induced by burns. Based on this belief and our transcriptional findings, we hypothesize that administration of agents that biodistribute to the inner membrane of mitochondria and reduce this oxidative stress by scavenging ROS will aid in normalizing burn induced metabolic alterations. The tetra peptide SS31 (D-Arg-Dmt-Lys-Phe-NH2) is an extremely potent mitochondrial-targeted ROS scavenger and thus a particularly promising candidate molecule to test this hypothesis. In this project, we plan to evaluate the effects of SS31 relative to a comparable tetra peptide (SS20), which does not scavage ROS, but has protective effects. In SA1, we will study the effects of SS31 on burn induced physiological alterations in glucose metabolism, TCA cycle activity, and mitochondrial membrane potential in mice. In SA2, we will determine SS31 and SS20 correlative effects on skeletal muscle gene expression in mice over time after burn injury utilizing the mouse transcriptome microarray, MJAY. In SA3, we will extend these investigations of the detailed genomic impact of SS31 treatment on gene expression with endotoxemia in Rhesus macaques, in healthy volunteers without endotoxemia, and in burn patients. SA1 and SA2 will provide genomic and physiologic mechanistic information in wild-type and MCAT (over-expression of catalase) burn-injured mice. SA3 will provide simultaneous genomic and physiologic information in non-human primates for both SS20 and SS31, and SS31 in burn patients.
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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