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

氧化还原对代谢和线粒体生物能学的控制指导急性炎症和脓毒症的进程

• 批准号: 10001885
• 负责人: Charles Emory McCall
• 金额: $ 14.42万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001885
• 关键词: Acute; Animals; Bioenergetics; Cardiac; Cells; Citric Acid Cycle; Clinical Trials; Code; Cysteine; Data; Dichloroacetate; Disease; Epigenetic Process; Equilibrium; Functional disorder; Glucose; Goals; Health Care Costs; Heart; Heart failure; Histopathology; Human; Hydrogen Peroxide; Immune; Immunity; Indirect Calorimetry; Inflammation; Inflammatory; Invaded; Lead; Maps; Mediator of activation protein; Metabolic; Metabolism; Mitochondria; Molecular; Multiple Organ Failure; Mus; Muscle strain; Myocardium; Nuclear; Organ; Organ failure; Organism; Oxidation-Reduction; PDH kinase; Paralysed; Pathologic; Pathway interactions; Phenotype; Play; Pre-Clinical Model; Production; Proteins; Proteomics; Public Health; Publishing; Pyruvate Dehydrogenase Complex; Recovery; Research; Resistance; Resolution; Role; SIRT1 gene; Sepsis; Septic Shock; Shock; Sulfhydryl Compounds; Testing; Tissues; Trauma; Ultrasonography; base; economic cost; global health; indexing; insight; metabolomics; novel; oxidation; pathogen; peroxiredoxin; programs; septic; theories; tool

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.

摘要 急性炎症，防止入侵病原体和 严重创伤使用两种截然不同的生存策略：抵抗和容忍。我们的研究 寻求确定作为稳态调节剂的分子轴，以重置 败血症炎性休克时的平衡阻力和耐受性。并在以下方面发挥重要作用 病理性炎症存活。我们之前发现NAD+1核sirtuins 1和2是 表观遗传和线粒体丙酮酸脱氢酶复合体(PDC)作为葡萄糖氧化 重新设置将中间代谢和免疫与合成代谢和免疫相结合的稳态药物 分解代谢能量学。这两条途径都支持败血症小鼠的存活。我们的初步数据 支持增加二氯乙酸酯(DCA)对PDC的刺激，从而促进存活 在脓毒症小鼠中，逆转超声评估的心肌应变，降低 分解代谢衣康酸，并利用三氯乙酸合成代谢能量。本R35一年期补充资料 将检验统一的概念，即半胱氨酸硫醇的可逆氧化和还原 败血症心脏的心脏组织蛋白重置阻力和耐受能量。我们的工具 将包括使用新型氧化还原探针的组织病理学、靶向代谢组学、氧化还原 蛋白质组学、高分辨率超声波和小型动物代谢室。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特定点。 完成补充将为扩大氧化还原阻力和 耐受性控制的概念，以其他器官已知，以限制败血症生存。