Exploring the origins of myelin abnormalities in normal ageing and in vascular dementia
Exploring the origins of myelin abnormalities in normal ageing and in vascular dementia
批准号:
10186055
负责人:
Margaret E Flanagan
金额:
$221.12万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-05-01 至 2024-04-30
关键词:
AdultAgeAgingAllelesAlzheimer&aposs DiseaseAnimalsAutopsyBehavioralBehavioral AssayBiological AssayBlood flowBrainCardiovascular AbnormalitiesCardiovascular DiseasesCardiovascular systemCell LineageCellsCellular StressCerebrovascular CirculationCerebrovascular DisordersCerebrovascular systemCognitionCognition DisordersCognitiveDementiaDevelopmentDiffuseEFRACElderlyEnvironmentEukaryotic CellFailureFunctional disorderGenesGenetic TranscriptionGliosisGoalsHealthHeart failureHigh Fat DietHumanHypertensionHypoxiaImpaired cognitionImpairmentIncidenceIndividualInflammationLeadLesionLinkMaintenanceMemoryMetabolicMetabolic syndromeMolecularMusMutant Strains MiceMutationMyelinNerve DegenerationNeurogliaNeurologicNeurologyNeuronsNitric Oxide SynthaseNutrientObesityOligodendrogliaOxidative StressOxygenPathogenesisPathologicPathway interactionsPharmacologyPlayPositioning AttributeProcessReportingRiskRoleSamplingSeriesStimulusStressTamoxifenTherapeuticTimeUniversitiesVascular DementiaVascular blood supplyWhite Matter DiseaseWorld Health Organizationbiological adaptation to stressbrain healthcell typecerebrovascularclinically relevantcomorbiditycytotoxicdementia riskdesignextracellulargenetic approachhypoxia inducible factor 1juvenile animalmouse modelneuropathologynormal agingnuclear factor-erythroid 2nutrient deprivationoligodendrocyte lineagepreservationresponsesextherapeutically effectivewhite matteryoung adult
中文摘要
根据世界卫生组织的数据,全球约有5000万人患有认知障碍。
紊乱痴呆症的发病率随着年龄的增长而增加,特别是对于65岁以上的人。CNS白色病变
也已知随着年龄的增长而增加,并增加患痴呆症的风险。血管性痴呆(VD)
是老年人认知异常的第二大常见原因,仅次于阿尔茨海默病(AD)。VD
与各种心血管疾病有关,这些疾病被认为是导致弥漫性白色物质
导致痴呆的疾病。这一提议的基本假设是,细胞毒性的影响,
与衰老和多种心血管疾病相关的CNS血管系统破坏所造成的环境
疾病对少突胶质细胞的活力和功能特别有害。我们认为,
少突胶质细胞由于其独特的代谢需求而表现出的对细胞应激的敏感性使得它们
特别容易受到随着年龄的增长而变化的细胞外环境的影响,
大脑循环的改变。作为以下原因的后果发生的白色异常
少突胶质细胞的扰动可能对神经退行性疾病、认知和行为的发展至关重要。
变化目前提案的目标是从机械上了解老龄化的影响,
脑血管异常对少突胶质细胞的影响,在人和小鼠模型中。我们的重点将放在
研究内在的细胞保护途径在少突胶质细胞对不良反应的反应中所起的作用,
由这些条件产生的细胞毒性环境。我们将重点关注三种细胞保护途径:
综合应激反应(ISR)途径是由多种应激启动的,包括氧化应激、缺氧
和炎症;核因子红细胞2相关因子2(NRF 2)途径被激活,
缺氧诱导因子1(HIF-1)途径是氧化应激的主要转录调节因子。
细胞缺氧反应我们将检查人类死后的样本,
在少突胶质细胞系细胞中激活这些通路,我们将类似地评估它们的
在衰老的小鼠中激活,这是已知的显示少突胶质细胞和髓鞘缺陷。我们还将
检查射血分数保留(HFpEF)心力衰竭小鼠模型的少突胶质细胞和髓鞘
与ISR、NRF 2和HIF激活相关的异常。HFpEF是一种常见的心血管异常
与痴呆症有关。我们还将使用遗传学方法进一步研究这些
衰老和脑血管异常造成的不利CNS环境的细胞保护途径。
总之,这些努力将大大增加我们对少突胶质细胞对药物反应的了解。
衰老和脑血管功能障碍造成的细胞毒性CNS环境。更好地欣赏
髓鞘生成胶质细胞功能障碍对痴呆发病机制的贡献对于我们理解
这一日益增长的健康问题,并可能作为设计的神经保护治疗策略的基础。
英文摘要
According to the World Health Organization approximately 50 million people worldwide suffer from cognitive
disorders. The incidence of dementia increases with age, especially for those over 65. CNS white matter lesions
are also known to increase with age and to increase the risk of developing dementia. Vascular dementia (VD) is
the second most common cause of cognitive abnormalities in the elderly behind Alzheimer’s disease (AD). VD
has been associated with various cardiovascular maladies, which are thought to contribute to diffuse white matter
disease leading to dementia. The underlying hypothesis of this proposal is that the impact of the cytotoxic
environment created by disruptions to the CNS vasculature associated with aging and diverse cardiovascular
disorders are particularly detrimental to oligodendrocyte viability and function. We posit that the heightened
sensitivity to cellular stress that oligodendrocytes display due to their unique metabolic demands makes them
particularly vulnerable to the changing extracellular environment that develops with advancing age and in
response an altered cerebral circulation. The white matter abnormalities that occur as a consequence of
oligodendrocyte perturbation are likely critical to the development of neurodegenerative, cognitive and behavioral
changes. The goal of the current proposal is to a gain a mechanistic understanding of the impact of ageing and
cerebrovascular abnormalities on oligodendrocytes, both in humans and in mouse models. Our focus will be on
examining the role that intrinsic cytoprotective pathways play in the response of oligodendrocytes to the adverse
cytotoxic environment created by these conditions. We will focus on three cytoprotective pathways: the
integrated stress response (ISR) pathway is initiated by a variety of stresses including oxidative stress, hypoxia
and inflammation; the nuclear factor erythroid 2-related factor 2 (NRF2) pathway is activated in response to
oxidative stress; and the hypoxia-inducible factor 1 (HIF-1) pathway is the master transcriptional regulator of the
cellular response to hypoxia. We will examine human postmortem samples from individuals with vascular
dementia for activation of these pathways in oligodendrocyte lineage cells, and we will similarly assess their
activation in ageing mice, which are known to display oligodendrocyte and myelin deficiencies. We will also
examine a mouse model of heart failure with preserved ejection fraction (HFpEF) for oligodendrocyte and myelin
abnormalities linked to ISR, NRF2 and HIF activation. HFpEF is a common cardiovascular abnormality
associated with dementia. We will also use a genetic approach to further examine the response of these
cytoprotective pathways to the adverse CNS environment created by ageing and cerebrovascular abnormalities.
Together, these efforts will substantially increase our understanding of the response of oligodendrocytes to the
cytotoxic CNS environment created by ageing and cerebrovascular dysfunction. A better appreciation of the
contribution of myelinating glia dysfunction to the pathogenesis of dementia is essential to our understanding of
this growing health concern and may serve as the basis for the design of neuroprotective therapeutic strategies.
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Neuropathology Core
-
批准号:10469450
-
项目类别:
-
资助金额:$42.21万
-
财政年份:2021
-
负责人:Margaret E Flanagan
-
依托单位:
Neuropathology Core
-
批准号:10662483
-
项目类别:
-
资助金额:$42.4万
-
财政年份:2021
-
负责人:Margaret E Flanagan
-
依托单位:
Neuropathology Core
-
批准号:10264371
-
项目类别:
-
资助金额:$47.42万
-
财政年份:2021
-
负责人:Margaret E Flanagan
-
依托单位:
nvestigating the role of neuroinflammation in Limbic-predominant age related TDP43 encephalopathy
-
批准号:10636935
-
项目类别:
-
资助金额:$16.38万
-
财政年份:2020
-
负责人:Margaret E Flanagan
-
依托单位:
Investigating the role of neuroinflammation in Limbic-predominant age related TDP43 encephalopathy
-
批准号:10439849
-
项目类别:
-
资助金额:$9.9万
-
财政年份:2020
-
负责人:Margaret E Flanagan
-
依托单位:
nvestigating the role of neuroinflammation in Limbic-predominant age related TDP43 encephalopathy
-
批准号:10820026
-
项目类别:
-
资助金额:$6.33万
-
财政年份:2020
-
负责人:Margaret E Flanagan
-
依托单位:
Investigating the role of neuroinflammation in Limbic-predominant age related TDP43 encephalopathy
-
批准号:10259658
-
项目类别:
-
资助金额:$16.3万
-
财政年份:2020
-
负责人:Margaret E Flanagan
-
依托单位:
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