This application continues our goal to identify molecular mechanisms that control sepsis, now defined as life threatening organ failure and infection. Potentially lethal sepsis rapidly changes from a transient activation state to a sustained inactivation state. The activation sepsis phase is anabolic, and the inactivation state is catabolic. Most sepsis deaths occur during the catabolic phase. We reported that NAD+ dependent nuclear SIRT1 and 6, and mitochondrial SIRT3 control monocyte anabolic activation and sustain catabolic inactivation during sepsis. We also reported persistent activation of pyruvate kinase 1 (PDHK1) during sepsis. PDHK1 activation blocks pyruvate's role in supporting mitochondrial respiration, and we have shown that inhibition PDHK1 activation rescues septic mice from death. As a potentially unifying control mechanism, we have discovered that oxidation of nuclear SIRT1 and 6, and mitochondrial PDHK1 cysteine (Cys) thiols occurs during anabolic activation and reduction of these thiol residues occurs during catabolic inactivation. Our unifying concept for this proposal is that Cys-thiol redox critically regulates sepsis prognosis. We propose two aims to develop this idea.
Aim 1 will determine how direct oxidation and reduction of SIRT1 and 6, and mitochondrial PDHK1 Cys-thiols regulates their function.
Aim 2 will determine how PDHK1 Cys-thiol oxidation and reduction regulates sepsis inflammation bioenergetics and influences its clinical outcome. Results from this project will identify new sepsis inflammation control mechanisms and inform new treatment targets.
Sepsis is a highly lethal disease with major global health and economic costs and has no available mechanism- based treatments. This has prompted a worldwide Public Health Crisis, with implementation for a program called Code Sepsis. Completing this research will provide mechanistic insight and inform new treatments, as accomplished with its initial funding cycle.
| Liu, Tie Fu; Vachharajani, Vidula T; Yoza, Barbara K et al. (2012) NAD+-dependent sirtuin 1 and 6 proteins coordinate a switch from glucose to fatty acid oxidation during the acute inflammatory response. J Biol Chem 287:25758-69 |
| Hoth, J Jason; Wells, Jonathan D; Hiltbold, Elizabeth M et al. (2011) Mechanism of neutrophil recruitment to the lung after pulmonary contusion. Shock 35:604-9 |
| Hoth, J Jason; Martin, R S; Yoza, Barbara K et al. (2009) Pulmonary contusion primes systemic innate immunity responses. J Trauma 67:14-21; discussion 21-2 |
