Redox control over metabolism and mitochondrial bioenergetics directs the course of acute inflammation and sepsis

总结 急性炎症，对抗来自入侵病原体的不受控制的环境威胁， 严重的创伤使用两种不同的生存策略：抵抗和容忍。我们的研究 试图确定分子轴，作为稳态重置分子途径， 在脓毒症炎症性休克时平衡抵抗和耐受。并发挥重要作用， 病理炎症存活率。我们先前鉴定了NAD+1核沉默调节蛋白1和2， 表观遗传和线粒体丙酮酸脱氢酶复合物（PDC）作为葡萄糖氧化 重置稳态，整合中间代谢和免疫与合成代谢和 分解代谢能量学两种途径都支持脓毒症小鼠的存活。我们的初步数据 支持二氯乙酸盐（DCA）增加PDC刺激，其促进存活 在败血症小鼠中，通过超声评估逆转心肌应变，降低 分解代谢衣康酸，并利用TCA合成代谢能量学。R35一年补充 将测试统一的概念，半胱氨酸硫醇的可逆氧化和还原， 心脏组织蛋白质重置脓毒症心脏的抵抗和耐受能量学。我们的工具 将包括使用新型氧化还原探针，靶向代谢组学，氧化还原 蛋白质组学、高分辨率超声和小动物代谢室。我们的实验 战略将首先建立概念证明，并确定氧化还原重置的具体点。 完成补充将为扩大氧化还原电阻奠定基础， 耐受性控制的概念，以其他器官已知限制败血症的生存。

Summary 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.