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.
|Zhao, Gaofeng; Yu, Yong-Ming; Kaneki, Masao et al. (2015) Simvastatin reduces burn injury-induced splenic apoptosis via downregulation of the TNF-?/NF-?B pathway. Ann Surg 261:1006-12|
|Watada, Susumu; Yu, Yong-Ming; Fischman, Alan J et al. (2014) Evaluation of intragastric vs intraperitoneal glucose tolerance tests in the evaluation of insulin resistance in a rodent model of burn injury and glucagon-like polypeptide-1 treatment. J Burn Care Res 35:e66-72|
|Zhao, Gaofeng; Yu, Yong-Ming; Shoup, Timothy M et al. (2014) Membrane potential-dependent uptake of 18F-triphenylphosphonium--a new voltage sensor as an imaging agent for detecting burn-induced apoptosis. J Surg Res 188:473-9|
|Carter, Edward A; Paul, Kasie; Bonab, Ali A et al. (2014) Effect of exercise on burn-induced changes in tissue-specific glucose metabolism. J Burn Care Res 35:470-3|
|Lee, Sangseok; Yang, Hong-Seuk; Sasakawa, Tomoki et al. (2014) Immobilization with atrophy induces de novo expression of neuronal nicotinic *7 acetylcholine receptors in muscle contributing to neurotransmission. Anesthesiology 120:76-85|
|Fu, Glenn K; Xu, Weihong; Wilhelmy, Julie et al. (2014) Molecular indexing enables quantitative targeted RNA sequencing and reveals poor efficiencies in standard library preparations. Proc Natl Acad Sci U S A 111:1891-6|
|Khan, Mohammed A S; Sahani, Nita; Neville, Kevin A et al. (2014) Nonsurgically induced disuse muscle atrophy and neuromuscular dysfunction upregulates alpha7 acetylcholine receptors. Can J Physiol Pharmacol 92:1-8|
|Ueda, Masashi; Iwasaki, Hajime; Wang, Shuxing et al. (2014) Cannabinoid receptor type 1 antagonist, AM251, attenuates mechanical allodynia and thermal hyperalgesia after burn injury. Anesthesiology 121:1311-9|
|Ibrahim, Amir; Fagan, Shawn; Keaney, Tim et al. (2014) A simple cost-saving measure: 2.5% mafenide acetate solution. J Burn Care Res 35:349-53|
|Shank, Erik S; Martyn, Jeevendra A; Donelan, Mathias B et al. (2014) Ultrasound-Guided Regional Anesthesia for Pediatric Burn Reconstructive Surgery: A Prospective Study. J Burn Care Res :|
Showing the most recent 10 out of 77 publications