Inflammation resolution, neuroprotection, and brain repair to promote stroke recovery
炎症消解、神经保护和大脑修复以促进中风康复
基本信息
- 批准号:10261320
- 负责人:
- 金额:$ 40.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-08-15 至 2022-05-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAcuteAdoptive TransferAdultAnti-Inflammatory AgentsAutoimmuneB-LymphocytesBehavioralBrainBrain DiseasesBrain InfarctionBrain InjuriesCD3 AntigensCD8B1 geneCXCR3 geneCell Culture TechniquesCell SeparationCellsCerebral IschemiaCognitiveDataDeteriorationDevelopmentDiffusion Magnetic Resonance ImagingDiseaseDistalDoseEconomic BurdenElectron MicroscopyElectrophysiology (science)EncephalitisEnvironmentEpidermal Growth FactorFosteringFunctional disorderGenderGenesGenetic TranscriptionGenomicsHarvestHistologicHomeHomeostasisIL2RA geneIL2RB geneImaging DeviceImmuneImmune responseImmune systemImmunohistochemistryImmunomodulatorsImmunotherapeutic agentIn VitroInfarctionInfiltrationInflammationInflammatoryInjuryInterleukin-10IschemiaIschemic Brain InjuryIschemic StrokeLIF geneLIFR geneLeadLightLymphocyteMediatingMemoryMiddle Cerebral Artery OcclusionModelingMolecularMusNamesNervous System PhysiologyNeurologic DeficitPathway interactionsPerformancePhasePilot ProjectsPlayPopulationProductionRegulatory T-LymphocyteResearchResolutionRodent ModelRoleSignal TransductionSliceStrokeT cell therapyT memory cellT-Cell DepletionT-LymphocyteTestingTherapeuticTransforming Growth FactorsUp-Regulationagedbrain repairclinically relevantclinically translatablecytokinefunctional outcomesgray matterimmunoregulationimprovedin vivo Modelinjury recoveryinterestleukemia inhibitory factor receptormaleneuroinflammationneurological recoveryneuroprotectionneurorestorationnovelnovel therapeutic interventionpost strokereconstitutionstroke outcomestroke recoverystroke therapytreatment strategywhite matter
项目摘要
Accumulating evidence implicates inflammation and immune responses in the pathophysiology of
stroke. Immunomodulation has therefore emerged as a promising therapy for stroke. Regulatory
lymphocytes, including CD4+CD25+ regulatory T cells (CD4+ Treg) and IL-10+ regulatory B cells (Bregs) are
established modulators of immune responses in the injured brain. We recently discovered that another
specialized T cell subpopulation—the CD8+CD122+CD49dhigh regulatory T cell—is among the first to enter
the ischemic brain, even preceding the infiltration of CD4+ Tregs and Bregs. The primary function of CD8+
Tregs is to modulate the activities of other immune cells, especially effector T lymphocytes, and to maintain
immune homeostasis. We found that selective depletion of circulating CD8+ Tregs exacerbated brain injury
and functional outcomes at 3 and 7 days after stroke, and this could be reversed by the reconstitution of
CD8+ Tregs. These exciting results suggest that CD8+ Tregs are natural defenders against ischemic brain
injury. Further pilot studies discovered that: 1) CD8+ Treg-afforded early protection relies on their infiltration
into the ischemic brain, as CD8+ Tregs lacking the “brain targeting signal” CXCR3 do not infiltrate into the
ischemic brain and lose their capacity to reduce brain infarction in CD8+ Treg-depleted mice. 2) The
infiltrated CD8+ Tregs undergo genomic reprogramming upon brain infiltration and transcriptional
upregulation of a group of genes that possess inflammation-resolving and/or neurorestorative functions,
including the leukemia inhibitory factor (LIF) receptor and epidermal growth factor-like transforming growth
factor (ETGF). 3) Post-stroke adoptive transfer of CD8+ Tregs significantly reduces brain infarct, enhances
white matter integrity, and improves neurological functions up to 14d after tMCAO. 4) Adoptive transfer of
ETGF-deficient CD8+ Treg fails to protect against tMCAO. The current proposal will further explore the effects
of CD8+ Tregs in ischemic stroke and develop CD8+ Treg adoptive transfer as an immune therapeutic therapy
for stroke. The novel central hypothesis to be tested is that brain infiltration of CD8+ Tregs promotes
long-term neurological recovery after stroke through LIF/LIFR/ETGF-mediated neuroprotection, resolution of
neuroinflammation, and neurorestorative mechanisms. Three specific aims are proposed. Aim 1. Establish
post-stroke adoptive transfer of CD8+ Tregs as a clinically relevant treatment against acute ischemic brain
infarct. Aim 2. Test the hypothesis that post-stroke adoptive transfer of CD8+ Tregs promotes long-term
neurological recovery and neurorestoration after ischemic stroke. Aim 3. Test the hypothesis that
LIF/LIFR-mediated release of ETGF is essential for CD8+ Treg-afforded neuroprotection and
neurorestoration. This study will be the first to rigorously investigate the role of CD8+ Tregs in ischemic brain
injury. The results will improve our understanding of stroke immunomodulation and shed light on CD8+ Treg
transfer as a potential therapeutic strategy.
越来越多的证据表明,炎症和免疫反应在炎症的病理生理学中起着重要作用。
中风因此,免疫调节已成为一种有前途的治疗中风。监管
淋巴细胞,包括CD 4 + CD 25+调节性T细胞(CD 4 + Treg)和IL-10+调节性B细胞(BCRs),
在受伤的大脑中建立了免疫反应的调节器。我们最近发现另一个
一种特殊的T细胞亚群--CD 8 + CD 122 + CD 49 dhigh调节性T细胞--是最早进入免疫系统的细胞之一。
缺血脑组织中CD 4 + T淋巴细胞和Bcl-2的浸润早于缺血脑组织中的T淋巴细胞和Bcl-2的浸润。CD 8+的主要功能
T淋巴细胞是调节其他免疫细胞,特别是效应T淋巴细胞的活动,并维持
免疫稳态我们发现循环中CD 8 + T淋巴细胞的选择性耗竭会加重脑损伤,
在中风后3天和7天的功能结果,这可以通过重建
CD 8 + T细胞。这些令人兴奋的结果表明,CD 8 + T细胞是缺血性脑损伤的天然防御者。
损伤进一步的初步研究发现:1)CD 8 + Treg的早期保护作用依赖于其浸润
由于缺乏“脑靶向信号”CXCR 3的CD 8 + T细胞不能浸润到缺血性脑中,
在CD 8 + Treg缺失小鼠中,它们可以减少缺血性脑并失去减少脑梗死的能力。2)的
浸润的CD 8 + T细胞在脑浸润和转录后经历基因组重编程
上调一组具有炎症消退和/或神经恢复功能的基因,
包括白血病抑制因子(LIF)受体和表皮生长因子样转化生长因子
因子(ETGF)。3)脑卒中后过继转移CD 8 + T细胞显著减少脑梗死,
白色物质的完整性,并改善神经功能长达14天后tMCAO。4)的过继转移
ETGF缺陷型CD 8 + Treg不能保护tMCAO。目前的建议将进一步探讨
CD 8 + Treg过继转移作为免疫治疗方法
治疗中风有待检验的新的中心假设是,CD 8 + T细胞的脑浸润促进了
通过LIF/LIFR/ETGF介导的神经保护作用,
神经炎症和神经修复机制。提出了三个具体目标。目标1.建立
脑卒中后过继转移CD 8 + T细胞作为急性缺血性脑损伤的临床相关治疗
梗塞目标2.检验卒中后过继转移CD 8 + T细胞是否促进长期的
缺血性卒中后的神经恢复和神经修复。目标3。测试的假设
LIF/LIFR介导的ETGF释放对于CD 8 + Treg提供的神经保护作用是必需的,
神经修复这项研究将是第一个严格研究CD 8 + T细胞在缺血性脑损伤中的作用的研究。
损伤这些结果将有助于我们对中风免疫调节的理解,并阐明CD 8 + Treg
转移作为一种潜在的治疗策略。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jun Chen其他文献
Corrosion wear characteristics of TC4, 316 stainless steel, and Monel K500 in artificial seawater
TC4、316不锈钢、蒙乃尔K500在人工海水中的腐蚀磨损特性
- DOI:
10.1039/c7ra03065g - 发表时间:
2017-04 - 期刊:
- 影响因子:3.9
- 作者:
Jun Chen - 通讯作者:
Jun Chen
Jun Chen的其他文献
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{{ truncateString('Jun Chen', 18)}}的其他基金
BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
- 批准号:
10696455 - 财政年份:2023
- 资助金额:
$ 40.83万 - 项目类别:
Adiponectin on cerebrovascular regulation in vascular cognitive impairment and dementia (VCID)
脂联素对血管性认知障碍和痴呆 (VCID) 的脑血管调节作用
- 批准号:
10542359 - 财政年份:2022
- 资助金额:
$ 40.83万 - 项目类别:
Activation of the RXR/PPARγ axis improves long-term outcomes after ischemic stroke in aged mice
RXR/PPARγ 轴的激活可改善老年小鼠缺血性中风后的长期结果
- 批准号:
10364171 - 财政年份:2022
- 资助金额:
$ 40.83万 - 项目类别:
Activation of the RXR/PPARγ axis improves long-term outcomes after ischemic stroke in aged mice
RXR/PPARγ 轴的激活可改善老年小鼠缺血性中风后的长期结果
- 批准号:
10609791 - 财政年份:2022
- 资助金额:
$ 40.83万 - 项目类别:
Methods for Analysis of Genomic Data with Auxiliary Information
具有辅助信息的基因组数据分析方法
- 批准号:
10188885 - 财政年份:2021
- 资助金额:
$ 40.83万 - 项目类别:
Methods for Analysis of Genomic Data with Auxiliary Information
具有辅助信息的基因组数据分析方法
- 批准号:
10415152 - 财政年份:2021
- 资助金额:
$ 40.83万 - 项目类别:
Inflammation resolution, neuroprotection, and brain repair to promote stroke recovery
炎症消解、神经保护和大脑修复以促进中风康复
- 批准号:
9471926 - 财政年份:2017
- 资助金额:
$ 40.83万 - 项目类别:
Inflammation resolution, neuroprotection, and brain repair to promote stroke recovery
炎症消解、神经保护和大脑修复以促进中风康复
- 批准号:
9697886 - 财政年份:2017
- 资助金额:
$ 40.83万 - 项目类别:
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