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

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.
项目总结 全身性炎症被认为是心理压力对健康造成破坏性影响的原因之一。在 实验室环境下,单一的急性社会评价应激导致PRO-2延迟升高。 健康成人中的炎性细胞因子。然而,心理压力产生的生物学机制 转化为炎症的机制还不是很清楚。一种已知的导致压力的细胞成分 信号是线粒体--一种源自细菌的细胞器,具有自己的基因组,即线粒体DNA (MtDNA)。最近的证据表明,各种应激源诱导线粒体释放- 衍生的信号分子,或有丝分裂素。丝裂原在系统中传播并调节中枢生理 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素 是循环中的无细胞线粒体DNA(ccf-mtdna),是线粒体排出mtdna的产物。 通过Toll样受体9(TLR-9),在动物和人类中导致促炎细胞因子的产生 细胞。我们的初步数据显示,ccf-mtdna的释放是强烈诱导的,而不是ccf-核dna。 在人类经历了短暂的实验性心理压力之后。因此,我们认为CCF-mtDNA可能是一种 在应激-炎症级联反应中缺失了一环。同时,对细胞系统进行成像和分子研究 提示CCF-mtDNA可能由主要的神经内分泌应激介质迅速诱导,包括 糖皮质激素。这项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应激访问,绘制CCF-mtDNA和CCF-mtDNA中反应和恢复的动力学图 健康女性和男性的其他压力调节剂。目标1将确定:i)CCF的大小和动力学- 线粒体DNA释放;ii)这种反应相对于核DNA的特异性;iii)检查潜在的性别 在这一过程中的差异;以及iv)统计检验CCF-mtDNA作为随后PRO增加的中介。 炎性细胞因子。在目标2中,细胞和分子研究将确定:i)原发的 糖皮质激素和儿茶酚胺应激激素足以触发原发性CCF-mtDNA的释放 人培养细胞和分离的白细胞;ii)活细胞mtDNA对应激反应的图像 信号;以及iii)记录有助于CCF-mtDNA释放的mtDNA结构的物理变化。最后, 目的3建立:i)峰值CCF-mtDNA血清中CCF-mtDNA激活细胞因子产生的能力。 靶细胞;ii)人血清中CCF-mtDNA的结构形式和可获得性(来自Aim 1);以及iii) 依赖TLR-9进行免疫激活。总体而言,这些研究将为 线粒体介导的人类应激转化为炎症的新机制。结果来自 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。

项目成果

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Brett A Kaufman其他文献

Brett A Kaufman的其他文献

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{{ truncateString('Brett A Kaufman', 18)}}的其他基金

Control of insulin secretion by mitochondrial fusion
通过线粒体融合控制胰岛素分泌
  • 批准号:
    10753730
  • 财政年份:
    2023
  • 资助金额:
    $ 68.36万
  • 项目类别:
Developing intrabody therapeutics for mitochondrial DNA heteroplasmy
开发线粒体 DNA 异质性的体内疗法
  • 批准号:
    10386997
  • 财政年份:
    2022
  • 资助金额:
    $ 68.36万
  • 项目类别:
Developing intrabody therapeutics for mitochondrial DNA heteroplasmy
开发线粒体 DNA 异质性的体内疗法
  • 批准号:
    10585928
  • 财政年份:
    2022
  • 资助金额:
    $ 68.36万
  • 项目类别:
Mitochondrial G-quadruplex structures in health and disease
健康和疾病中的线粒体 G-四链体结构
  • 批准号:
    10428535
  • 财政年份:
    2020
  • 资助金额:
    $ 68.36万
  • 项目类别:
Mitochondrial G-quadruplex structures in health and disease
健康和疾病中的线粒体 G-四链体结构
  • 批准号:
    10221730
  • 财政年份:
    2020
  • 资助金额:
    $ 68.36万
  • 项目类别:
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
  • 批准号:
    10574523
  • 财政年份:
    2019
  • 资助金额:
    $ 68.36万
  • 项目类别:
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
  • 批准号:
    10359137
  • 财政年份:
    2019
  • 资助金额:
    $ 68.36万
  • 项目类别:
Molecular mechanisms of mitochondrial DNA deletion formation
线粒体DNA缺失形成的分子机制
  • 批准号:
    9261548
  • 财政年份:
    2015
  • 资助金额:
    $ 68.36万
  • 项目类别:

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