Acute inflammation against uncontrolled environmental threats from invading pathogens and severe trauma uses two distinct survival strategies: resistance and tolerance. Our research seeks to identify molecular axes that act as homeostats to reset the molecular pathways that balance resistance and tolerance during sepsis inflammatory shock. and play a major role in pathologic inflammation survival. We previously identified NAD+1 nuclear sirtuins 1 and 2 as epigenetic and mitochondrial pyruvate dehydrogenase complex (PDC) as glucose oxidation resetting homeostats that integrate intermediary metabolism and immunity with anabolic and catabolic energetics. Both pathways support survival in septic mice. Our preliminary data support that increased PDC stimulation by the dichloroacetate (DCA), which promotes survival in septic mice, reverses heart muscle strain as assessed by ultrasound, reduces levels of catabolic itaconate, and harnesses TCA anabolic energetics. This R35 one year supplement will test the unifying concept that reversible oxidation and reduction of cysteine thiols in heart tissue proteins reset resistance and tolerance energetics in septic heart. Our tools will include tissue histopathology using novel redox probes, targeted metabolomics, redox proteomics, high resolution ultrasound, and small animal metabolic chambers. Our experimental strategy will first establish proof of concept and identify specific points of redox resetting. Completing the supplement will lay the groundwork for expanding the redox resistance and tolerance control concept to other organs known to limit sepsis survival.
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.
