Transduction of Psychological Stress into Systematic Inflammation by Mitochondrial DNA Signaling

通过线粒体 DNA 信号传导将心理压力转变成系统性炎症

基本信息

批准号：
9920214
负责人：
Brett A Kaufman
金额：
$ 68.36万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9920214
关键词：
Acute Adrenergic Receptor Adult Affect Animals Bacteria Biological Blood Blood Platelets Catecholamines Cell physiology Cells Chronic Cultured Cells DNA DNA Structure Data Deoxyribonucleases Dependence Disease Dose Epinephrine Event Exposure to Female Fibroblasts Foundations Functional disorder Genetic Genome Glucocorticoid Receptor Glucocorticoids Health Hormones Hour Human Hydrocortisone Image Immune Inflammation Inflammatory Inflammatory Response Injections Interleukin-6 Kinetics Laboratories Leukocytes Link Lymphocyte Major Depressive Disorder Maps Mediating Mediator of activation protein Membrane Mental Health Mental disorders Methods Mitochondria Mitochondrial DNA Molecular Molecular Structure Mus Nature Neurosecretory Systems Norepinephrine Nuclear Organelles Outcome Oxides Participant Pathway interactions Physiological Physiological Processes Physiology Plasma Positioning Attribute Process Production Psychological Stress Psychosocial Stress Receptor Signaling Recovery Research Personnel Rest Risk Role Rupture Series Serum Sex Differences Signal Pathway Signal Transduction Signaling Molecule Specificity Stress Structure Suicide attempt Supplementation System TLR9 gene TNF gene Testing Time Travel Trier Social Stress Test Visit Woman Work acute stress aged base cellular imaging circulating biomarkers cytokine digital disorder risk experience immune activation immunogenic immunogenicity improved inflammatory marker inhibitor/antagonist live cell imaging male men molecular marker monocyte negative affect neutrophil novel oxidation psychologic psychosocial response secondary analysis stressor volunteer

项目摘要

PROJECT SUMMARY Systemic inflammation is believed to contribute to the damaging health effects of psychological stress. In the laboratory setting, a single acute bout of socioevaluative stress leads to a delayed elevation of pro- inflammatory cytokines in healthy adults. However, the biological mechanisms by which psychological stress is transduced into inflammation is not well understood. A cellular component known to contribute to stress signaling is the mitochondrion – a bacteria-derived organelle with its own genome, the mitochondrial DNA (mtDNA). Recent evidence has demonstrated that various stressors induce the release of mitochondria- derived signaling molecules, or mitokines. Mitokines travel systemically and modulate central physiological processes, including immune cell function and the production of pro-inflammatory cytokines. One key mitokine is circulating cell-free mtDNA (ccf-mtDNA), which arises from mitochondrial extrusion of mtDNA, is recognized by the toll-like receptor 9 (TLR-9), and leads to pro-inflammatory cytokine production in animal and human cells. Our preliminary data showed that ccf-mtDNA release, but not ccf-nuclear DNA, is acutely induced following a brief experimental psychological stress in humans. Thus, we suggest that ccf-mtDNA may be a missing link in the stress-inflammation cascade. In parallel, imaging and molecular studies on cellular systems suggests that ccf-mtDNA may be rapidly induced by primary neuroendocrine stress mediators, including glucocorticoids. This proposal will use an experimental socio-evaluative stress task, counterbalanced with a control no-stress visit for each participant, to map the kinetics of reactivity and recovery in ccf-mtDNA and other stress mediators in healthy women and men. Aim 1 will establish: i) the magnitude and kinetics of ccf- mtDNA release; ii) the specificity of this response compared to nuclear DNA; iii) examine potential sex differences in this process; and iv) statistically test ccf-mtDNA as a mediator of the subsequent increase in pro- inflammatory cytokines. In Aim 2, cellular and molecular studies will determine: i) whether primary glucocorticoid and catecholamine stress hormones are sufficient to trigger ccf-mtDNA release in primary human cultured cells and isolated leukocytes; ii) image in living cells mtDNA release in response to stress signaling; and iii) document physical changes in mtDNA structure that contribute to ccf-mtDNA release. Finally, Aim 3 will establish: i) the capacity of ccf-mtDNA from peak ccf-mtDNA serum to activate cytokine production in target cells; ii) the structural form and accessibility of ccf-mtDNA in human serum (from Aim 1); and iii) the dependency on TLR-9 for immune activation. Overall, these studies will contribute mechanistic evidence for a novel mitochondria-mediated mechanisms for transducing stress into inflammation in humans. Outcomes from this work will identify new potential targets to improve stress-related mental health and inflammatory disorders.

项目摘要据信系统性炎症会导致心理压力的健康影响。在实验室环境，一次社会评估应力的一次急性急性发作导致促进健康成年人的炎性细胞因子。但是，心理压力的生物学机制转导为炎症尚不清楚。已知有助于应力的细胞成分信号传导是线粒体 - 具有其自身基因组的细菌衍生细胞体，线粒体DNA （mtDNA）。最近的证据表明，各种压力诱导线粒体的释放派生的信号分子或有丝分子。有丝分子系统地旅行并调节中央生理过程，包括免疫细胞功能和促炎细胞因子的产生。一个关键的有丝分裂因子是由mtDNA的线粒体扩展产生的循环无细胞mtDNA（CCF-MTDNA）。通过Toll样受体9（TLR-9），并导致动物和人类的促炎性细胞因子产生细胞。我们的初步数据表明，CCF-MTDNA释放而不是CCF - 核DNA是急性诱导的在人类中短暂的实验心理压力之后。那我们建议CCF-MTDNA可能是缺少应力炎症级联中的链接。同时，对细胞系统的成像和分子研究表明CCF-MTDNA可能是由原发性神经内分泌应激介体迅速诱导的，包括糖皮质激素。该建议将使用实验性的社会评估压力任务，与控制每个参与者的无压力访问，以绘制CCF-MTDNA中反应性和恢复的动力学健康男女的其他压力介体。 AIM 1将建立：i）CCF-的大小和动力学 mtDNA释放； ii）与核DNA相比，这种反应的特异性； iii）检查潜在的性别这个过程的差异； iv）统计测试CCF-MTDNA作为随后增加的介体炎症细胞因子。在AIM 2中，细胞和分子研究将确定：i）糖皮质激素和儿茶酚胺胁迫恐怖足以触发初级中的CCF-MTDNA释放人培养的细胞和分离的白细胞； ii）活细胞中的图像mtDNA响应应力而释放信号传导； iii）记录有助于CCF-MTDNA释放的mtDNA结构的物理变化。最后， AIM 3将建立：i）CCF-MTDNA从峰CCF-MTDNA血清激活细胞因子在中的能力靶细胞； ii）CCF-MTDNA在人血清中的结构形式和可及性（来自AIM 1）；和iii）对TLR-9的依赖性免疫激活。总体而言，这些研究将为A提供机理证据新型的线粒体介导的机制，将应激转换为人类炎症。结果这项工作将确定新的潜在目标，以改善与压力相关的心理健康和炎症性疾病。