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:
- 金额:$ 68.36万
- 依托单位:
- 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:
- 关键词:AcuteAdrenergic ReceptorAdultAffectAnimalsBacteriaBiologicalBloodBlood PlateletsCatecholaminesCell physiologyCellsChronicCultured CellsDNADNA StructureDataDeoxyribonucleasesDependenceDiseaseDoseEpinephrineEventExposure toFemaleFibroblastsFoundationsFunctional disorderGeneticGenomeGlucocorticoid ReceptorGlucocorticoidsHealthHormonesHourHumanHydrocortisoneImageImmuneInflammationInflammatoryInflammatory ResponseInjectionsInterleukin-6KineticsLaboratoriesLeukocytesLinkLymphocyteMajor Depressive DisorderMapsMediatingMediator of activation proteinMembraneMental HealthMental disordersMethodsMitochondriaMitochondrial DNAMolecularMolecular StructureMusNatureNeurosecretory SystemsNorepinephrineNuclearOrganellesOutcomeOxidesParticipantPathway interactionsPhysiologicalPhysiological ProcessesPhysiologyPlasmaPositioning AttributeProcessProductionPsychological StressPsychosocial StressReceptor SignalingRecoveryResearch PersonnelRestRiskRoleRuptureSeriesSerumSex DifferencesSignal PathwaySignal TransductionSignaling MoleculeSpecificityStressStructureSuicide attemptSupplementationSystemTLR9 geneTNF geneTestingTimeTravelTrier Social Stress TestVisitWomanWorkacute stressagedbasecellular imagingcirculating biomarkerscytokinedigitaldisorder riskexperienceimmune activationimmunogenicimmunogenicityimprovedinflammatory markerinhibitor/antagonistlive cell imagingmalemenmolecular markermonocytenegative affectneutrophilnoveloxidationpsychologicpsychosocialresponsesecondary analysisstressorvolunteer
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
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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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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