Integrative translational discovery of vascular risk factors in aging and dementia
衰老和痴呆血管危险因素的综合转化发现
基本信息
- 批准号:9001610
- 负责人:
- 金额:$ 532.73万
- 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:2015-09-30 至 2020-05-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAgeAgingAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease riskAmyloidAmyloid depositionAnimal ModelApolipoprotein EAstrocytesAtherosclerosisAutopsyBlood - brain barrier anatomyBlood VesselsBrainCellsCerebral Amyloid AngiopathyCerebrovascular CirculationCerebrumClinicClinicalCognitiveCollectionDataDementiaDepositionDevelopmentDiabetes MellitusDiagnosisDiagnosticDiseaseDisease modelElderlyEnvironmental Risk FactorEpidemiologic StudiesEpigenetic ProcessEstrogen Replacement TherapyEstrogensFemaleFunctional disorderGenesGeneticGenomeGenomicsGenotypeGoalsGonadal Steroid HormonesHumanHypertensionImpaired cognitionImpairmentIncidenceIndividualInjuryIntracranial AtherosclerosesIntracranial HemorrhagesKentuckyKnowledgeLesionMeasuresMediatingMetabolismMethodologyMethylationModelingMolecularMusNerve DegenerationNeurodegenerative DisordersOutcomeOvariectomyPathogenesisPathologyPathway interactionsPatientsPerfusionPhasePhenotypePlayPrevalenceProtein IsoformsRNA SequencesRiskRisk FactorsRoleSenile PlaquesSeveritiesSeverity of illnessSex CharacteristicsSignal TransductionStagingStrokeSystemTestingUniversitiesVascular DiseasesVascular SystemWorkabeta accumulationage relatedagedamyloid pathologyapolipoprotein E-3apolipoprotein E-4basecerebrovascularcerebrovascular lesioncognitive functioncohortepidemiologic dataepigenomeepigenomicsexome sequencinggenetic associationgenetic risk factorhigh riskinduced pluripotent stem cellinsightinterdisciplinary approachmalemild cognitive impairmentmouse modelneuroimagingneuropathologynext generationnovelpublic health relevancesextau Proteinstherapeutic targettranscriptome sequencing
项目摘要
DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the deposition of amyloid-β (Aβ) in the brain parenchyma as senile plaques and in the cerebrovasculature as cerebral amyloid angiopathy (CAA). CAA is also a major cause of intracranial hemorrhage in the elderly. Epidemiological studies indicate that disturbance of the vascular system contributes to the pathogenesis of both AD and CAA. In addition, the ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for both AD and CAA. ApoE4 exacerbates Aβ accumulation in the brain, causes blood-brain barrier breakdown and reduction of small vessels. While APOE4 carriers have a higher risk for AD in general, APOE4 effect is significantly stronger in females compared to males. Consistently, our preliminary results indicate that APOE4 has a stronger genetic association with CAA severity in females than males. Although females have a higher risk for AD, we found that males have more severe CAA than females in AD. These data suggest the presence of sex-specific, and both apoE-dependent and independent molecular pathways in the development of CAA and AD. In this proposal, we aim to define how sex and apoE isoforms differentially affect the risk for AD and CAA, and to identify novel genes and pathways that contribute to cerebrovascular pathology in aging and AD. We will use interdisciplinary, systems-based approaches by leveraging existing and generating new data in neuropathology, genome/epigenome, and neuroimaging fields in richly phenotyped, large autopsy brain collections and the longitudinally followed, elderly cohort, Mayo Clinic Study of Aging (MCSA). Our comprehensive hypothesis-driven and hypothesis-generating studies will provide novel insights into the molecular mechanisms underlying CAA and other cerebrovascular pathologies in AD. Our specific aims are as follows: Aim 1. Define the effects of sex and apoE isoforms on the pathological distribution and severity of CAA and parenchymal amyloid plaques; Aim 2. Identify novel pathways that contribute to the development of CAA and AD; Aim 3. Discover the impact of novel pathways on vascular risk in aging and dementia; Aim 4. Investigate the molecular mechanisms mediating the impact of apoE isoforms and estrogen on brain Aβ clearance and the formation of CAA and amyloid plaques. Collectively, these studies are expected to both uncover mechanisms underlying apoE and sex effects for AD/CAA and discover novel genes and pathways that will be candidate diagnostic and therapeutic targets.
描述(由申请人提供):阿尔茨海默氏病(AD)是一种进行性神经退行性疾病,其特征是淀粉样蛋白-β(Aβ)在脑实质中沉积为老年斑,并且在脑血管系统中沉积为脑淀粉样血管病(CAA)。流行病学研究表明,血管系统紊乱是 AD 的发病机制之一。此外,载脂蛋白 E (APOE) 基因的 ε4 等位基因是 AD 和 CAA 的最强遗传风险因素。一般来说,APOE4 携带者患 AD 的风险较高,但与男性相比,APOE4 的效应在女性中明显更强。尽管如此,我们的初步结果表明,与男性相比,APOE4 与女性 CAA 严重程度的遗传指示相关性更强。女性患 AD 的风险更高,我们发现男性患 AD 的 CAA 比女性更严重,这些数据表明在 CAA 和 AD 的发展中存在性别特异性、apoE 依赖和独立的分子途径。根据该提案,我们的目标是确定性别和 apoE 异构体如何对 AD 和 CAA 的风险产生不同的影响,并确定有助于衰老和 AD 脑血管病理学的新基因和途径。生成神经病理学、基因组/表观基因组和神经影像学领域的新数据,包括丰富的表型、大型尸检脑样本以及纵向跟踪的老年队列、梅奥诊所衰老研究 (MCSA),我们全面的假设驱动和假设生成研究将提供新颖的研究。深入了解 AD 中 CAA 和其他脑血管病理的分子机制,我们的具体目标如下: 目标 1. 明确性别和 apoE 亚型对病理分布的影响。目标 2. 确定导致 CAA 和 AD 发展的新途径;目标 3. 发现新途径对衰老和痴呆的血管风险的影响;目标 4. 研究介导的分子机制; apoE 异构体和雌激素对大脑 Aβ 清除以及 CAA 和淀粉样斑块形成的影响 总的来说,这些研究有望揭示 apoE 和性别影响的潜在机制。 AD/CAA 并发现新的基因和途径,这些基因和途径将成为候选诊断和治疗靶点。
项目成果
期刊论文数量(0)
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{{ truncateString('GUOJUN BU', 18)}}的其他基金
TREM2-mediated microglial dynamic function in Alzheimer disease
TREM2 介导的阿尔茨海默病小胶质细胞动态功能
- 批准号:
10088365 - 财政年份:2020
- 资助金额:
$ 532.73万 - 项目类别:
TREM2-mediated microglial dynamic function in Alzheimer disease
TREM2 介导的阿尔茨海默病小胶质细胞动态功能
- 批准号:
9914464 - 财政年份:2020
- 资助金额:
$ 532.73万 - 项目类别:
Integrative translational discovery of vascular risk factors in aging and dementia
衰老和痴呆血管危险因素的综合转化发现
- 批准号:
9421402 - 财政年份:2017
- 资助金额:
$ 532.73万 - 项目类别:
ApoE isoform-specific therapy for Alzheimer disease
ApoE 异构体特异性治疗阿尔茨海默病
- 批准号:
8894356 - 财政年份:2013
- 资助金额:
$ 532.73万 - 项目类别:
ApoE isoform-specific therapy for Alzheimer disease
ApoE 异构体特异性治疗阿尔茨海默病
- 批准号:
9104070 - 财政年份:2013
- 资助金额:
$ 532.73万 - 项目类别:
ApoE isoform-specific therapy for Alzheimer disease
ApoE 异构体特异性治疗阿尔茨海默病
- 批准号:
8744260 - 财政年份:2013
- 资助金额:
$ 532.73万 - 项目类别:
ApoE isoform-specific therapy for Alzheimer disease
ApoE 异构体特异性治疗阿尔茨海默病
- 批准号:
9291405 - 财政年份:2013
- 资助金额:
$ 532.73万 - 项目类别:
ApoE isoform-specific therapy for Alzheimer disease
ApoE 异构体特异性治疗阿尔茨海默病
- 批准号:
8608893 - 财政年份:2013
- 资助金额:
$ 532.73万 - 项目类别:
BRAIN LIPID METABOLISM, DENDRITES AND SYNAPSES IN AGING AND ALZHEIMER'S DISEASE
衰老和阿尔茨海默病中的脑脂质代谢、树突和突触
- 批准号:
8183828 - 财政年份:2010
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$ 532.73万 - 项目类别:
BRAIN LIPID METABOLISM, DENDRITES AND SYNAPSES IN AGING AND ALZHEIMER'S DISEASE
衰老和阿尔茨海默病中的脑脂质代谢、树突和突触
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8206522 - 财政年份:2010
- 资助金额:
$ 532.73万 - 项目类别:
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