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:9471926
- 负责人:
- 金额:$ 40.75万
- 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:AcuteAdoptive Cell TransfersAdoptive TransferAdultAnti-Inflammatory AgentsAnti-inflammatoryAutoimmune ProcessB-LymphocytesBehavioralBrainBrain DiseasesBrain InfarctionBrain InjuriesCD3 AntigensCD8B1 geneCXCR3 geneCell Culture TechniquesCell SeparationCellsCerebral IschemiaCognitiveDataDeteriorationDevelopmentDiffusion Magnetic Resonance ImagingDiseaseDistalDoseEconomic BurdenElectron MicroscopyElectrophysiology (science)Employee StrikesEncephalitisEnvironmentEpidermal Growth FactorFosteringFunctional disorderGenderGenesGenetic TranscriptionGenomicsHarvestHistologicHome environmentHomeostasisIL2RA geneIL2RB geneImaging DeviceImmuneImmune responseImmune systemImmunohistochemistryIn VitroInfarctionInfiltrationInflammationInflammatoryInjuryInterleukin-10IschemiaIschemic Brain InjuryIschemic StrokeLIF geneLIFR geneLeadLightLymphocyteMediatingMemoryMiddle Cerebral Artery OcclusionModelingMolecularMusNamesNervous System PhysiologyNeurologic DeficitOutcomePathway interactionsPerformancePhasePilot ProjectsPlayPopulationProductionRecoveryRegulatory T-LymphocyteResearchResolutionRodent ModelRoleSignal TransductionSliceStrokeT memory cellT-LymphocyteTestingTherapeuticTransforming Growth FactorsUp-Regulationagedbrain repairclinically relevantclinically translatablecytokinefunctional outcomesgray matterimmunoregulationimprovedin vivo Modelinterestleukemia inhibitory factor receptormaleneuroinflammationneurological recoveryneuroprotectionneurorestorationnovelnovel therapeuticspost strokereconstitutionstroke 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.
越来越多的证据暗示炎症和免疫反应在病理生理
项目成果
期刊论文数量(0)
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:
$ 40.75万 - 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:
$ 40.75万 - 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:
$ 40.75万 - 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:
$ 40.75万 - 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:
$ 40.75万 - 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:
$ 40.75万 - 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:
10261320 - 财政年份:2017
- 资助金额:
$ 40.75万 - 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:
$ 40.75万 - 项目类别:














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