Metabolic disturbances remain a significant cause of morbidity and mortality of burn patients, despite advancements in the resuscitation and surgical treatment. These aberrations include hypermetabolism, protein catabolism, aberrant fuel preference (predominant oxidafion of fatty acid over glucose), and muscle wasting. Insulin resistance has been postulated as a key player in burn-induced metabolic derangements. Conversely, metabolic derangements have been proposed as an inducer and/or enhancer of insulin resistance, as well. The IRS-1-Akt-Fox01/3 pathway plays a central role in metabolic acfions of insulin in skeletal muscle. Activation of Fox01/3 promotes protein degradation and muscle wasting, and inhibits glucose oxidation in skeletal muscle. In addition to attenuated Akt activity, FoxO transcription factors are activated by MST1 protein kinase and O-glycosylation. The preliminary data in skeletal muscle of burn patients and burned rodents indicate that: (1) IRS-1 expression is suppressed, while the expression of PTP- 1B, a negative regulator of insulin signaling, is increased;(2) serine phosphorylation of IRS-1 is increased: and (3) activities of FoxOI/3 and expression ofthe target genes of FoxOs are increased along with decreased Akt activity and increased stimulatory signals (MST1 activity, O-glycosylation). Based on previous studies and our solid preliminary data, we hypothesize that activation of FoxOI/3, which results from attenuated Akt activity, increased MST1 activity, and O-glycosylation, plays an important role in burn injuryinduced metabolic derangements, and that FoxOs-mediated metabolic disturbances contribute to exacerbafion of impaired IRS-l-mediated insulin signaling in skeletal muscle after burn injury.
Specific Aim 1 will establish attenuated IRS-1-mediated signaling, and clarify serine/threonine phosphorylation status of IRS-1 in muscle of burn patients.
Specific Aim 2 will determine the role of FoxOI and Fox03 in metabolic derangements, specifically muscle wasting and oxidation of glucose versus fatty acid, and in impaired IRS-1- Akt signaling in muscle of burn patients and burned mice, using muscle-specific FoxOI or Fox03 knockout mice.
Specific Aim 3 will determine the safety and efficacy of antisense morpholino oligomers (PMOs) targeting PTP-1 B, FoxOI, and Fox03 in burned mice. Rhesus monkeys, and burn patients. This project is designed to determine whether PTP-1 B, FoxOI, and Fox03 are clinically relevant molecular targets to reverse insulin resistance and metabolic disturbances in burn patients. The proposed studies are expected to develop a new antisense PMO-based therapeutic strategy to improve the outcome of burn patients.
Metabolic disturbances remain a signficant cause of morbidity and mortality in burn patients. New knowledge gained in this project should promote potential new genomic-based therapeutics to reduce the complications associated with dysregulated metabolism in burn patients.
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