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Effect of Mitochondrial Quality Control on Systemic Inflammation and Organ Dysfunction in Pediatric Sepsis

线粒体质量控制对小儿脓毒症全身炎症和器官功能障碍的影响

基本信息

批准号：
10029859
负责人：
SCOTT L WEISS
金额：
$ 54.71万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10029859
关键词：
Address Animal Model Antibiotics Biogenesis Caring Cause of Death Cell Respiration Cell physiology Cells Cessation of life Child Childhood Clinical Cytosol Data Enrollment Etiology Event Functional disorder Future Genetic Transcription Goals Health Hospitalization Human Human Herpesvirus 4 Immune Immune response In Vitro Infection Inflammasome Inflammation Inflammatory Injury Investigation Lead Life Link Lipopolysaccharides Measures Medical emergency Metabolic Mitochondria Mitochondrial DNA Mitochondrial Diseases Mitochondrial RNA Multiple Organ Failure National Institute of Child Health and Human Development Organ Oxidation-Reduction Pathologic Pathway interactions Patients Pattern Peripheral Blood Mononuclear Cell Plasma Prevention Process Proteins Protocols documentation Quality Control Recovery Refractory Regulation Respiration Resuscitation Sampling Sepsis Septic Shock Severities Shock Speed Stimulator of Interferon Genes Suggestion TLR9 gene Testing Therapeutic United States Work body system cytokine experimental study high risk improved in vitro Model interest lipoteichoic acid lymphoblast mitochondrial dysfunction protein expression septic systemic inflammatory response targeted treatment therapeutic target

项目摘要

PROJECT SUMMARY / ABSTRACT Sepsis is a medical emergency of life-threatening organ dysfunction due to a dysregulated host response to infection. In the United States, over one million people are hospitalized with sepsis or septic shock every year, including >75,000 children. Multiple organ dysfunction syndrome (MODS) is the most common cause of death for children with sepsis. Although most children who develop sepsis recover with appropriate conventional care, ~20% develop MODS, and one in five of these children with sepsis-induced MODS still die. For this high-risk subset, we have no cure and care is largely supportive. Widespread alterations in the ability of mitochondria to supply sufficient energy for normal cellular activities has been implicated as a key pathologic event leading to MODS in sepsis. Using a protocol optimized to measure mitochondrial respiration and content in peripheral blood mononuclear cells (PBMC), our group discovered that children with prolonged sepsis- induced MODS are more likely to have persistent mitochondrial dysfunction. This proposal builds on our prior work to test the hypothesis that low mitochondrial respiration in PBMCs is caused by abnormal mitochondrial quality control processes (biogenesis, fission, fusion, and mitophagy) that normally restore and maintain mitochondrial health. The resulting mitochondrial dysfunction, through release of mitochondrial DNA (mtDNA) into the cytosol, can then activate inflammatory pathways that sustain inflammation and organ dysfunction in children with sepsis. In Aim 1, we will determine which changes in mitochondrial quality control are associated with recovery versus persistence of low mitochondrial respiration in children with sepsis. We will enroll 106 children with sepsis-induced MODS and measure mitochondrial respiration, redox state, content, biogenesis, fission, fusion, and mitophagy on days 1, 3, 5, and 7 of illness. In Aim 2, we will determine if the persistence of PBMC mitochondrial dysfunction activates three inflammatory pathway (cGAS-STING, TLR-9, and inflammasome) that sense release of mtDNA into the cytosol. In Aim 3, we will test whether mitochondrial dysfunction, abnormal mitochondrial quality control, or activation of inflammatory pathways are associated with the severity or duration of MODS in children with sepsis. As part of Aims 1 and 2, we will also conduct a parallel set of in vitro experiments to test the utility of lipopolysaccharide- and lipoteichoic acid-stimulation of EBV-transformed lymphoblasts as a potential translational platform for future therapeutic investigation and to establish cytosolic mtDNA as one mechanism through which mitochondria can promote inflammation in sepsis. These aims address the NICHD’s interest in “studies focused on mitochondrial dysfunction as a pathophysiologic process of MODS…with potential to advance to translational and clinical projects.” By understanding why mitochondrial dysfunction persists in some children and how this can lead to sustained inflammation and MODS, we will identify new potential therapeutic targets for children with prolonged MODS, the leading cause of death in sepsis for which we currently have no cure.

项目摘要/摘要