The Kaneki laboratory has been working on stress (e.g., burn injury)-induced insulin resistance, mitochondrial dysfunction and muscle wasting. In the attempt to clarify the underlying molecular mechanisms and help develop a clinical trial in burn patients, the lab uses genetically engineered mice, pharmacological approaches and cell culture system. In addition, the PI conducted a pilot clinical study of coenzyme Q10 in burn patients, based on the data in burned mice. At present, related to stress-induced insulin resistance and metabolic derangements the following project is ongoing:

Mechanisms by which burn injury induces insulin resistance and metabolic derangements. Metabolic derangements, including insulin resistance, mitochondrial dysfunction and hyperlactatemia, are a major complication of burn injury and negatively affect clinical outcomes of burn patients. However, the molecular mechanisms by which burn injury induces these metabolic derangements remain to be clarified. We have shown that: (1) burn injury increases farnesyltransferase expression and farnesylated proteins; and (2)

farnesyltransferase inhibitor (FTI) prevents burn-induced insulin resistance (which parallels reversal of increased basal [insulin-unstimulated] mTORC1 activation), mitochondrial dysfunction in mouse skeletal muscle and hyperlactatemia. We have also shown that burn injury induces the Warburg effect in mouse skeletal muscle, as indicated by increases in expression of hypoxia-inducible factor (HIF)-1α and its downstream glycolytic genes, which is prevented by FTI. Moreover, we have recently shown that FTI prevents sepsis-induced mitochondrial damage in mice. (Sepsis is a leading cause of mortality in burn patients.) In addition, we have reported that treatment with coenzyme Q10 prevents burn-induced metabolic aberrations (i.e., insulin resistance, mitochondrial dysfunction and hyperlactatemia) in mice. Based on these data, the PI conducted a pilot clinical study in burn patients (ClinicalTrials.gov Identifier: NCT02251626).