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
新生儿(围产期)动脉缺血性卒中是长期神经和认知功能障碍的主要原因
缺陷,包括脑瘫和神经发育障碍。虽然新生儿中风
在老年人中很常见,文献已经出现了大脑发育的阶段,
中风对脑损伤的病理生理学机制具有重大影响。先前
治疗努力主要集中在急性保护神经元,但这些策略似乎
短距离。我们报道了延迟鼻内注射间充质干细胞(MSC)
保护白色物质并改善长期功能结果的实验模型,
新生大鼠短暂性大脑中动脉闭塞(tMCAO)。细胞外囊泡(EV)现在
被认为在细胞间通讯中起着重要作用,而在健康的人中没有直接的细胞间接触。
和患病的生物体,EV是神经退行性疾病的一部分。根据我们初步的
从MSC释放的外泌体(MSC-exo)保护亚急性中风后新生儿大脑的数据,
我们假设MSC-exo是MSC诱导急性心肌梗死的潜在机制。
通过调节小胶质细胞信号传导,在新生儿中风后提供神经保护和长期恢复。
鉴于炎症是围产期脑损伤的标志,影响早期损伤和脑修复,
以及小胶质细胞有助于新生儿的神经和血管保护。
中风,我们将确定如何摄取非经鼻管理MSC-exo的激活
缺血再灌注区小胶质细胞/巨噬细胞对新生儿神经炎症和损伤的影响
两种性别的小鼠进行tMCAO和MSC-exo是否改变脑微环境,
从小胶质细胞中释放微泡和小EV(目的1),并确定
MSC-exo给药对髓鞘形成、脑修复和功能结局的影响(目的2)。了解
MSC-exo的机制作用及其对新生儿卒中的治疗潜力,我们将利用国家-
最先进的实验工具,包括临床相关的围产期局灶性动脉卒中模型,
与药理学方法和先进的非侵入性成像技术相结合,
方法(NanoSight,超分辨率流式细胞术Alexa)和大/小细胞的表征
EV和它们的“货物”从受伤区域的小胶质细胞释放出来。的重要性和新奇,
提出的研究是在推进机制的理解,MSC外诱导的细胞类型,
在新生儿脑卒中后的具体影响,并确定新的治疗目标,以创造有效的
安全的治疗方法。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
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
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
- 批准号:
MR/Z503605/1 - 财政年份:2024
- 资助金额:
$ 44.41万 - 项目类别:
Research Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
- 批准号:
2336167 - 财政年份:2024
- 资助金额:
$ 44.41万 - 项目类别:
Standard Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
- 批准号:
2402691 - 财政年份:2024
- 资助金额:
$ 44.41万 - 项目类别:
Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
- 批准号:
24K12150 - 财政年份:2024
- 资助金额:
$ 44.41万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
- 批准号:
2341428 - 财政年份:2024
- 资助金额:
$ 44.41万 - 项目类别:
Standard Grant
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
- 批准号:
DE240100561 - 财政年份:2024
- 资助金额:
$ 44.41万 - 项目类别:
Discovery Early Career Researcher Award
RUI: Evaluation of Neurotrophic-Like properties of Spaetzle-Toll Signaling in the Developing and Adult Cricket CNS
RUI:评估发育中和成年蟋蟀中枢神经系统中 Spaetzle-Toll 信号传导的神经营养样特性
- 批准号:
2230829 - 财政年份:2023
- 资助金额:
$ 44.41万 - 项目类别:
Standard Grant
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
- 批准号:
23K09542 - 财政年份:2023
- 资助金额:
$ 44.41万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
- 批准号:
23K07552 - 财政年份:2023
- 资助金额:
$ 44.41万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
- 批准号:
23K07559 - 财政年份:2023
- 资助金额:
$ 44.41万 - 项目类别:
Grant-in-Aid for Scientific Research (C)