Delayed cognitive impairment after stroke
中风后迟发性认知障碍
基本信息
- 批准号:8539106
- 负责人:
- 金额:$ 19.04万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-09-01 至 2014-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAgeAlzheimer&aposs DiseaseAnimal ModelAnimalsAntibodiesAntigen PresentationAppearanceAreaAutoantibodiesAutoimmune ProcessB-LymphocytesBehavioral SymptomsBrainCellsCerebrovascular DisordersCholesterolCognitionCognitiveCognitive deficitsComplement ActivationDataDementiaDetectionDevelopmentDiabetes MellitusDiagnosisDiseaseDistalDrug TargetingExploratory/Developmental GrantExposure toFDA approvedFunctional disorderFundingFutureGoalsHeavy-Chain ImmunoglobulinsHippocampus (Brain)HourHumanHypertensionHypoxiaImmunohistochemistryImpaired cognitionInbred BALB C MiceIncidenceInfarctionInflammationInflammatory ResponseIschemiaKnockout MiceLeadLearningLesionLigationLinkMS4A1 geneMeasuresMediatingMediator of activation proteinMemoryMemory impairmentMental DepressionMiddle Cerebral Artery OcclusionModelingMouse StrainsMusNeurodegenerative DisordersOutcomeOxygenPatientsPhenotypePlasmaProcessProductionQuality of lifeRiskRisk FactorsRodentShort-Term MemoryStrokeStructureSurvivorsSwimmingT-Cell ActivationTailTemperatureTestingTimeTransgenic MiceVascular DementiaVeinsWorkbasebehavior testchemokinecohortconditioned fearcytokinemiddle cerebral arterymorris water mazemouse modelneuroinflammationneurotoxicneurotoxicitynovelpost strokepreventpublic health relevanceresearch studyresponserituximabsham surgerystroke recovery
项目摘要
DESCRIPTION (provided by applicant): Cerebrovascular disease is a major risk factor for dementia. All-cause dementia, (vascular dementia, Alzheimer's disease, and mixed disorders) is diagnosed in up to 48% of stroke survivors, with about 20% incidence in the first year after stroke. Several stroke risk factors, including hypertension, high cholesterol, diabetes, and age, also independently increase the risk of dementia. But multiple studies demonstrate that even after controlling for risk factors, stroke alone still doubles the risk of new onset dementia. We propose to model how stroke increases the risk of developing dementia by developing a new mouse model where stroke causes delayed cognitive dysfunction. In our model mice undergo DH stroke as a result of distal middle cerebral artery occlusion followed by hypoxia. This confers a primarily cortical infarct. Mice display normal working memory 8 days after stroke but by 6-7 weeks later they develop deficits in working and spatial memory, accompanied by a prolonged inflammatory response. A part of this inflammatory response is the appearance of B cells in the stroke core, in follicle-like structures. Such structures in the CNS have recently been linked to several neurodegenerative diseases. We propose here to develop our model and test whether B cells are pathogenic in our model. In Aim 1 we will use a panel of cognitive tests at key timepoints to assess which areas of cognition are affected in this model, and also carefully phenotype the delayed inflammatory response to stroke. We hypothesize that pathogenic features of neuroinflammation will precede or coincide with cognitive impairment. In Aim 2 we will use a B cell-depleting antibody and B cell knockout mice to ask whether B cells are required for cognitive dysfunction to occur. This work has high potential to produce significant impact because there are currently no well-accepted models and little is known about the genesis of this common and debilitating disorder. At the conclusion of these experiments we will have characterized the cognitive deficit and inflammatory responses in our model and will know whether B cells are causative. This information will allow us to pursue critical future studies on the mechanisms that underlie post-stroke dementia, and in addition will provide a way to test potential therapies.
描述(由申请人提供):脑血管疾病是痴呆症的主要危险因素。全因痴呆症(血管性痴呆,阿尔茨海默氏病和混合疾病)被诊断出多达48%的中风幸存者,中风后的第一年发病率约为20%。几个中风危险因素,包括高血压,高胆固醇,糖尿病和年龄,也独立增加了痴呆症的风险。但是多项研究表明,即使在控制危险因素之后,单独的中风仍然使新发作痴呆症的风险增加一倍。我们建议通过开发一种新的小鼠模型,导致延迟认知功能障碍来建模中风如何增加痴呆症的风险。在我们的模型中,小鼠由于脑远端脑动脉阻塞而经历DH中风,然后是缺氧。这主要是皮质梗塞。中风后8天表现出正常的工作记忆,但到6-7周后,它们会出现工作和空间记忆的缺陷,并伴随着长时间的炎症反应。这种炎症反应的一部分是在卵泡样结构中的中风核中B细胞的出现。中枢神经系统中的此类结构与几种神经退行性疾病有关。我们在这里建议开发我们的模型并测试B细胞在我们的模型中是否具有致病性。在AIM 1中,我们将在关键时刻使用一组认知测试来评估该模型中哪些认知领域受到影响,并仔细表型对中风的炎症反应延迟。我们假设神经炎症的致病特征将在认知障碍之前或一致。在AIM 2中,我们将使用B细胞耗尽的抗体和B细胞敲除小鼠询问是否需要B细胞才能发生认知功能障碍。这项工作具有产生重大影响的高潜力,因为目前尚无良好的模型,并且对这种常见和使人衰弱的疾病的起源知之甚少。在这些实验的结论中,我们将表征我们模型中认知缺陷和炎症反应的表征,并知道B细胞是否是病因。这些信息将使我们能够对势力后痴呆症基础的机制进行批判性的未来研究,此外,还将提供一种测试潜在疗法的方法。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Does B lymphocyte-mediated autoimmunity contribute to post-stroke dementia?
- DOI:10.1016/j.bbi.2016.08.009
- 发表时间:2017-08
- 期刊:
- 影响因子:0
- 作者:Doyle KP;Buckwalter MS
- 通讯作者:Buckwalter MS
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MARION S BUCKWALTER其他文献
MARION S BUCKWALTER的其他文献
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{{ truncateString('MARION S BUCKWALTER', 18)}}的其他基金
Spleen glia in autonomic regulation of immunity
脾胶质细胞在免疫自主调节中的作用
- 批准号:
9317544 - 财政年份:2016
- 资助金额:
$ 19.04万 - 项目类别:
TGFbeta signaling, reactive astrogliosis and function after stroke
TGFbeta 信号传导、反应性星形胶质细胞增生和中风后的功能
- 批准号:
8453563 - 财政年份:2012
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$ 19.04万 - 项目类别:
TGFbeta signaling, reactive astrogliosis and function after stroke
TGFbeta 信号传导、反应性星形胶质细胞增生和中风后的功能
- 批准号:
8845261 - 财政年份:2011
- 资助金额:
$ 19.04万 - 项目类别:
TGFbeta signaling, reactive astrogliosis and function after stroke
TGFbeta 信号传导、反应性星形胶质细胞增生和中风后的功能
- 批准号:
8656157 - 财政年份:2011
- 资助金额:
$ 19.04万 - 项目类别:
TGFbeta signaling, reactive astrogliosis and function after stroke
TGFbeta 信号传导、反应性星形胶质细胞增生和中风后的功能
- 批准号:
8231396 - 财政年份:2011
- 资助金额:
$ 19.04万 - 项目类别:
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