White matter restoration and functional recovery after experimental stroke
实验性卒中后白质恢复和功能恢复
基本信息
- 批准号:9054320
- 负责人:
- 金额:$ 33.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-09-15 至 2020-06-30
- 项目状态:已结题
- 来源:
- 关键词:Action PotentialsAcuteAdultAlteplaseAmino Acid SubstitutionAnti-Inflammatory AgentsAnti-inflammatoryAntioxidantsAxonBehaviorBindingBlood - brain barrier anatomyBrainCell Differentiation processCerebral IschemiaCerebral hemisphere hemorrhageClinicalCoculture TechniquesCognitive deficitsCorpus CallosumDataDemyelinationsDistalDoseEpidermal Growth Factor ReceptorExternal CapsuleFDA approvedFailureFibrinolytic AgentsGenerationsGenesHumanInfarctionInjuryInterventionIntranasal AdministrationIntraventricular InfusionIschemic StrokeKnockout MiceLeadMediatingMembraneMiddle Cerebral Artery OcclusionModelingMusMyelinMyelin SheathMyelinated nerve fiberNervous System PhysiologyNeuritesNeurologicNeurological outcomeNeuronsOligodendrogliaPatientsPeptide HydrolasesPeroxisome Proliferator-Activated ReceptorsPlayPrevention therapyProcessRecoveryRecovery of FunctionRegenerative responseResearchRiskRodent ModelRoleSerine ProteaseStrokeSystemTestingTherapeuticTimeagedaxonal sproutingcognitive testingdeprivationdisabilityimprovedin vivoinjuredmutantmyelinationneurological recoveryneurorestorationneurotransmissionnoveloligodendrocyte precursoroverexpressionpost strokeprecursor cellpublic health relevancereceptorremyelinationrepairedrestorationstroke therapythrombolysiswhite matterwhite matter injuryyoung adult
项目摘要
DESCRIPTION (provided by applicant): White matter (WM) injury, characterized by demyelination and loss of axonal integrity, is an important cause of long-term sensorimotor and cognitive deficits after stroke. WM repair, including axonal regrowth, oligodendrogenesis and the myelination of demyelinated or newly generated axons, would help rebuild neuronal connectivity and reestablish axonal signal conduction. Unfortunately, the adult brain has limited capacity for remyelination, at least in part due to the failure of differentiation of oligodendrocyte precursor cells (OPCs) into mature, myelinating oligodendrocytes (OLs). Thus, interventions that promote OPC differentiation may facilitate axonal remyelination, WM repair and long-term neurological recovery in stroke patients. Human recombinant tissue plasminogen activator (tPA) is the only FDA approved drug for the thrombolytic treatment of ischemic stroke. However, recent research has discovered various neuroprotective effects by tPA that are independent of its thrombolytic activity. Moreover, intranasal administration of tPA improves functional recovery and promotes axonal sprouting after stroke. Currently, the use of tPA is limited to the first 4.5 hr after the oset of stroke, as beyond this time window it tremendously increases the risk of intracerebral hemorrhage (ICH) via BBB damage. This proposal will investigate the efficacy of tPAm, a mutant form of tPA that lacks thrombolytic activity (thus would not induce ICH), in rodent models of ischemic stroke. We have found in primary cultures that tPAm potently promotes the differentiation of OPCs into mature OLs. This effect of tPAm depends on its activation of PPAR, a master transcriptional factor that regulates cell differentiation and possesses antioxidant and anti-inflammatory functions. In vivo studies suggest that lack of endogenous tPA exacerbates functional deficits and WM injury up to 35 days after distal MCAO. In contrast, tPAm administration 6 hr after transient MCAO improved long-term neurological behavior and WM integrity. Our results suggest that tPAm enhances post-stroke WM integrity, at least in part, by promoting OPC differentiation and axonal myelination. This proposal will investigate the novel WM repair-enhancing role of tPAm and the underlying mechanisms. We will test the following overarching hypothesis: Treatment with protease-inactive tPAm facilitates WM repair and long-term neurological recovery after stroke, at least in part by promoting OPC differentiation and axonal myelination through PPAR. Both young adult and aged mice will be tested. Three Specific Aims are proposed. Aim 1: Determine whether post-stroke treatment with the protease-inactive tPAm enhances WM integrity and promotes long-term neurological recovery. Aim 2: Test the hypothesis that tPAm induces OPC differentiation/maturation and promotes axonal myelination via PPAR activation. Primary OPCs and a neuron-OPC co-culture system will be applied to test this hypothesis. Aim 3: Test the hypothesis that tPAm-induced OPC differentiation and axonal myelination/remyelination are essential for its beneficial effects on WM integrity and long-term neurological recovery after stroke.
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
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10696455 - 财政年份:2023
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$ 33.69万 - 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
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10542359 - 财政年份:2022
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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:
$ 33.69万 - 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:
$ 33.69万 - 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:
$ 33.69万 - 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:
$ 33.69万 - 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:
$ 33.69万 - 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:
$ 33.69万 - 项目类别:
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