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与脑血管病的病理生理学有关
卒中。因此,免疫调节疗法已成为治疗中风的一种很有前途的疗法。监管
淋巴细胞,包括CD4+CD25+调节性T细胞(CD4+Treg)和IL-10+调节性B细胞(Bregs)
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
专门的T细胞亚群-CD8+CD122+CD49d高调节性T细胞-是最早进入的
脑缺血,甚至先于CD4+Tregs和Bregs的渗透。CD8+的主要功能
Tregs是调节其他免疫细胞,特别是效应性T淋巴细胞的活性,并维持
免疫动态平衡。我们发现选择性地耗尽循环中的CD8+Tregs会加重脑损伤
和卒中后3天和7天的功能结果,这种情况可以通过重建
CD8+树突状细胞。这些令人兴奋的结果表明,CD8+Tregs是脑缺血的天然防御者
受伤。进一步的初步研究发现:1)CD8+Treg的早期保护依赖于它们的渗透
由于CD8+Tregs缺乏“脑靶向信号”,CXCR3不会渗透到缺血的大脑中。
在CD8+Treg耗尽的小鼠中,它们可以减少脑缺血,并失去减少脑梗塞的能力。2)
浸润性CD8+Tregs在脑内渗透和转录时进行基因组重编程
一组具有消炎和/或神经恢复功能的基因上调,
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(ETGF)。3)卒中后CD8+Tregs过继转移明显减少脑梗塞,增强
白质完整性,并改善神经功能,直到tMCAO后14d。4)收养转让
ETGF缺乏的CD8+Treg不能预防tMCAO。目前的提案将进一步探讨其影响
CD8+Treg在缺血性卒中中的应用及CD8+Treg过继转移作为免疫治疗的研究
治疗中风。有待检验的新中心假设是,CD8+Tregs的大脑渗透促进了
卒中后通过LIF/LIFR/ETGF介导的神经保护的长期神经恢复,解决
神经炎症和神经恢复机制。提出了三个具体目标。目标1.建立
卒中后CD8+Tregs过继移植治疗急性脑缺血的临床研究
脑梗塞。目的2.验证中风后CD8+Tregs过继移植促进长期治疗的假说
缺血性卒中后的神经功能恢复和神经功能恢复。目标3.检验假设
LiF/LIFR介导的ETGF释放对CD8+Treg提供的神经保护和
神经修复。这项研究将首次严格研究CD8+Tregs在脑缺血中的作用
受伤。这一结果将提高我们对中风免疫调节的理解,并为CD8+Treg的研究提供线索
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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