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

基本信息

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
项目类别：
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

项目摘要

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.

概括急性炎症针对不受控制的环境威胁，侵略性病原体和严重的创伤使用了两种不同的生存策略：抵抗和耐受性。我们的研究试图识别作为体内体的分子轴，以重置分子途径败血症炎症性休克期间的平衡性和耐受性。并在病理炎症存活。我们以前以前确定了NAD+1核素1和2 表观遗传学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，将中介代谢和免疫力与合成代谢和免疫力整合在一起分解代谢能力。两种途径都支持化粪池中的生存。我们的初步数据支持增加了二氯乙酸（DCA）的PDC刺激，从而促进生存在化粪池小鼠中，通过超声评估的逆转心肌菌株，降低了水平分解代谢式酸，并利用TCA合成代谢能力。此R35一年补充将测试统一的概念，即可逆氧化和减少半胱氨酸硫醇心脏组织蛋白在化脓性心脏中复位耐药性和耐受能量。我们的工具将包括使用新型氧化还原探针，靶向代谢组，氧化还原的组织组织病理学蛋白质组学，高分辨率超声和小动物代谢室。我们的实验策略将首先建立概念证明，并确定氧化还原重置的特定点。完成补充剂将为扩大氧化还原电阻和耐受性控制概念对已知会象败血症存活的其他器官。