Exosomes as the mechanism of mesenchymal stem cell brain repair in neonatal stroke
外泌体作为间充质干细胞脑修复新生儿中风的机制
基本信息
- 批准号:10373763
- 负责人:
- 金额:$ 44.41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-15 至 2024-02-29
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdultAffectAgeBehaviorBlood - brain barrier anatomyBrainBrain Hypoxia-IschemiaBrain InjuriesCell CommunicationCell TherapyCellsCerebral PalsyCognitive deficitsCommunicationContralateralDataDevelopmentDiseaseDisease modelElderlyExperimental ModelsFailureFamilyFlow CytometryFractionationHistologicHumanInfantInfarctionInflammationInjuryInterventionIntranasal AdministrationLeukocyte TraffickingLifeLiteratureLive BirthLong-Term EffectsMediatingMesenchymal Stem CellsMethodologyMicrogliaMiddle Cerebral Artery OcclusionModelingMusNeonatalNerve DegenerationNervous System PhysiologyNeurodegenerative DisordersNeurodevelopmental DisabilityNeurologic DeficitNeuronsOligodendrogliaOrganismOutcomePerinatalPerinatal Brain InjuryPharmacologyPlayProteinsRattusRecoveryReperfusion TherapyReportingResearchResolutionRodentRoleSensorimotor functionsSeveritiesSignal TransductionSocietiesSourceSpinal cord injuryStrokeStructure of choroid plexusTerm BirthTestingTherapeuticTimeTraumatic Brain InjuryVascular remodelingVesiclebasebrain repaircell typechemokineclinically relevantcostcytokinedisabilityeffective therapyexosomeextracellular vesiclesfunctional outcomesimprovedinjuredinjury and repairinnovationmacrophagemicrovesiclesmyelinationneonatal brainneonatal hypoxic-ischemic brain injuryneonatal miceneonatal strokeneurobehaviorneuroinflammationneuron lossneuroprotectionnew therapeutic targetnon-invasive imagingnovelnovel therapeutic interventionperinatal ischemic strokepost strokepostnatalpreservationpuprepairedrestorationsexsham surgerystem cell exosomesstem cell survivalstroke clinical trialsstroke modeltherapeutically effectivetooluptakewhite matter
项目摘要
Abstract
Neonatal (perinatal) arterial ischemic stroke is a major cause of long-term neurological and cognitive
deficits, including cerebral palsy and neurodevelopmental disabilities. While neonatal stroke is as
common as in the elderly, literature has emerged that the stage of brain development at the time of
stroke has a major impact on the pathophysiological mechanisms of brain damage. Previous
therapeutic efforts were mostly focused on protecting neurons acutely, but such strategies appeared to
be short-range. We reported that delayed intranasal administration of mesenchymal stem cells (MSC)
protects the white matter and improves long-term functional outcomes in an experimental model of a
transient middle cerebral artery occlusion (tMCAO) in neonatal rats. Extracellular vesicles (EV) are now
believed to play fundamental role in cell-cell communication without direct cell-cell contacts in healthy
and diseased organism and that EV is a part of neurodegenerative scenarios. Based on our preliminary
data that exosomes released from MSC (MSC-exo) protect neonatal brain following subacute stroke, in
this proposal we hypothesize that MSC-exo is the underlying mechanism of MSC-induced acute
neuroprotection and long-term recovery after neonatal stroke via modulation of microglial cell signaling.
Given that inflammation is a hallmark of perinatal brain injury, affecting both early injury and brain repair
and connectivity later in life, and that microglial cells contribute to neuro- and vasoprotection in neonatal
stroke, we will determine how uptake of untranasally administered MSC-exo by activated
microglia/macrophages in ischemic-reperfused regions affects neuroinflammation and injury in neonatal
mice of both sexes subjected to tMCAO and whether MSC-exo alter brain microenvironment via
release of microvesicles and small EV from microglia (Aim 1), and determine the long-term effects of
MSC-exo administration on myelination, brain repair and functional outcomes (Aim 2). To understand
the mechanistic role of MSC-exo and their therapeutic potential for neonatal stroke, we will utilize state-
of-the art experimental tools, including a clinically relevant perinatal focal arterial stroke model that we
invented, in conjunction with pharmacological approaches and advanced non-invasive imaging
methodologies (NanoSight, super resolution flow cytometry Alexa) and characterization of large/small
EV and their “cargo” released from microglia from injured regions. The significance and novelty of the
proposed studies are in advancing the mechanistic understanding of MSC-exo-induced cell-type
specific effects in neonatal brain after stroke and identifying novel therapeutic targets to create effective
and safe therapy for neonatal stroke.
摘要
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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Zinaida S Vexler其他文献
Transient Middle Cerebral Occlusion Produces Severe Injury to The Neonatal(P7) Rat Brain † 1905
- DOI:
10.1203/00006450-199804001-01928 - 发表时间:
1998-04-01 - 期刊:
- 影响因子:3.100
- 作者:
Zinaida S Vexler;Nikita Derugin;Timothy PL Roberts;R Ann Sheldon;George Gregory;Donna M Ferriero - 通讯作者:
Donna M Ferriero
c-Jun N-Terminal Kinase (JNK) Activation after Transient MCA Occlusion in Neonatal Brain
- DOI:
10.1203/00006450-199904020-02069 - 发表时间:
1999-04-01 - 期刊:
- 影响因子:3.100
- 作者:
Zinaida S Vexler;Kanji Muramatsu;Nikita Derugin;R Ann Sheldon;George Gregory;Donna M Ferriero - 通讯作者:
Donna M Ferriero
Zinaida S Vexler的其他文献
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{{ truncateString('Zinaida S Vexler', 18)}}的其他基金
Hemorrhagic transformation associated with delayed reperfusion in perinatal and childhood ischemic stroke: brain maturation-dependent role of leukocytes
与围产期和儿童缺血性卒中延迟再灌注相关的出血性转化:白细胞的脑成熟依赖性作用
- 批准号:
10811475 - 财政年份:2023
- 资助金额:
$ 44.41万 - 项目类别:
Childhood stroke: effects of infection-induced arteriopathies
儿童中风:感染引起的动脉病的影响
- 批准号:
10329941 - 财政年份:2018
- 资助金额:
$ 44.41万 - 项目类别:
Childhood stroke: effects of infection-induced arteriopathies
儿童中风:感染引起的动脉病的影响
- 批准号:
10084326 - 财政年份:2018
- 资助金额:
$ 44.41万 - 项目类别:
Perinatal stroke: effects of bioactive lipids on immune-neurovascular axis and brain repair
围产期中风:生物活性脂质对免疫神经血管轴和脑修复的影响
- 批准号:
10064968 - 财政年份:2017
- 资助金额:
$ 44.41万 - 项目类别:
Leukocyte trafficking through the choroid plexus as modulator of neonatal focal stroke
白细胞通过脉络丛的运输作为新生儿局灶性中风的调节剂
- 批准号:
9188681 - 财政年份:2016
- 资助金额:
$ 44.41万 - 项目类别:
Blood-brain barrier function after neonatal and pediatric experimental stroke
新生儿和儿童实验性卒中后的血脑屏障功能
- 批准号:
8358551 - 财政年份:2012
- 资助金额:
$ 44.41万 - 项目类别:
Macrophages as modulators of repair after neonatal stroke
巨噬细胞作为新生儿中风后修复的调节剂
- 批准号:
8469921 - 财政年份:2012
- 资助金额:
$ 44.41万 - 项目类别:
Macrophages as modulators of repair after neonatal stroke
巨噬细胞作为新生儿中风后修复的调节剂
- 批准号:
8862546 - 财政年份:2012
- 资助金额:
$ 44.41万 - 项目类别:
Macrophages as modulators of repair after neonatal stroke
巨噬细胞作为新生儿中风后修复的调节剂
- 批准号:
8371152 - 财政年份:2012
- 资助金额:
$ 44.41万 - 项目类别:
Blood-brain barrier function after neonatal and pediatric experimental stroke
新生儿和儿童实验性卒中后的血脑屏障功能
- 批准号:
8469106 - 财政年份:2012
- 资助金额:
$ 44.41万 - 项目类别:
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