Big data and small molecules for Alzheimer's disease
阿尔茨海默病的大数据和小分子
基本信息
- 批准号:10217833
- 负责人:
- 金额:$ 41.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-15 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:Administrative SupplementAgeAlzheimer&aposs DiseaseAlzheimer&aposs disease patientAlzheimer&aposs disease therapeuticAnatomyAstrocytosisBig DataBiological MarkersBloodBlood - brain barrier anatomyBlood VesselsBrainBrain MappingBrain PathologyBrain imagingC-reactive proteinChromosome 17ClinicalCombined Modality TherapyDatabasesDisease ProgressionExhibitsFTD with parkinsonismFunctional disorderFundingGeneticGlial Fibrillary Acidic ProteinGoalsHarvestHealthHumanImageImpairmentIntercellular adhesion molecule 1Interleukin-6InterventionKnowledgeLinkMass Spectrum AnalysisMethodsMicrovascular DysfunctionModelingMusNerve DegenerationNeurofibrillary TanglesOnset of illnessPathogenesisPathologicPathologyPatternPharmaceutical PreparationsPharmacologyPhenotypePlasmaReportingResolutionResourcesSerum amyloid A proteinStainsTauopathiesTechniquesTechnologyTestingTransgenic MiceTreatment EfficacyUnited States Department of Veterans AffairsVascular Cell Adhesion Molecule-1VeteransWorkbasecerebrovascular healthclinical translationclinically relevantclinically translatabledata warehousedesignefficacy testingimaging biomarkerinnovationmolecular markermouse modelmutantneuroimagingneuroinflammationneuron lossnovel therapeuticsparent projectpre-clinicalsmall moleculetau Proteinstau mutationtau-1
项目摘要
Abstract
The goal of this administrative supplement application is to use our high resolution metallomic imaging
mass spectrometry (hr-MIMS) for brain mapping of microvascular impairment associated with the pathogenesis
and progression of Alzheimer's disease (AD). Specifically, we propose to perform phenotype analyses conducted
under our NIA-funded RF1 project (“Big Data and Small Molecules for Alzheimer's Disease” 1RF1AG063913-
01) by applying innovative, state-of-the-art mass spectrometry techniques to characterize brain phenotypic
endpoints. The funded RF1 parent project is designed to identify specific ACEI+STAT medications in a large
national database and test the efficacy of ACEI+STAT combination therapy to suppress pathological phenotypes
in tauopathy mouse models. In this supplement proposal, we will add phenotype analysis in the same mouse
model. We will investigate brain microvascular impairment and corresponding imaging and biomarkers linked to
tauopathy pathogenesis and progression. The rationale for broadening project scope is supported by: (i) clinical
evidence linking vascular pathologies with AD; (ii) new findings from the collaborating PIs (and others) that point
to microvasculopathy and blood-brain barrier (BBB) dysfunction as key drivers of tau protein pathology and
progression, (iii) recent acquisition of state-of-the-art mouse neuroimaging and mass spectrometry resources
that enable translation of clinically-relevant brain imaging for eventual use in humans. The new aim leverages
the same well-characterized tauopathy mouse models (P301L mice expressing mutant human tau) included in
the funded parent project. This model exhibits progressive microvasculopathy, tauopathy, and
neurodegeneration relevant to AD pathogenesis and progression. We will systematically investigate the temporal
and spatial patterning of brain pathologies with added focus on microvascular dysfunction and relationship to
corresponding neuroimaging. We plan to achieve one Aim to test our hypothesis that tauopathy,
microvasculopathy and neuronal loss can be tracked by metallomic imaging and staining of biomarkers of brain
vascular health. We aim to investigate temporal, anatomical, and mechanistic linkage among tauopathy and
microvasculopathy in a genetic AD mouse model expressing mutant human P301L tau. Sub-Aim 1A: Evaluate
brain microvasculopathy by molecular marker profiling (SAA, CRP, VCAM-1, ICAM-1) and high-resolution
metallomic imaging mass spectrometry (hr-MIMS) brain mapping in a tauopathy model as a function of age and
disease progression. Sub-Aim 1B: Correlate results from Sub-Aim 1A with quantitative immunohistochemical
analysis of harvested brains targeting key pathological endpoints (phosphorylated tauopathy, p-tau/tau;
neuroinflammation, Iba-1; astrocytosis, GFAP; neuronal loss) relevant to progression of tauopathy. We will test
whether microvascular-BBB dysfunction will anatomically colocalize and mechanistically link with progression of
tauopathy in the mouse model.
摘要
这个行政补充申请的目标是使用我们的高分辨率金属成像
质谱法(hr-MIMS)用于与发病机制相关的微血管损伤的脑绘图
和阿尔茨海默病(AD)的进展。具体来说,我们建议进行表型分析,
根据我们的国家情报局资助的RF 1项目(“大数据和小分子阿尔茨海默病”1 RF 1AG 063913-
01)通过应用创新的、最先进的质谱技术来表征大脑表型,
端点。资助的RF 1父项目旨在确定大规模的特定ACEI+STAT药物,
国家数据库,并测试ACEI+STAT联合治疗抑制病理表型的疗效
在tau蛋白病小鼠模型中。在本补充提案中,我们将在同一小鼠中添加表型分析
模型我们将研究脑微血管损伤和相应的成像和生物标志物与
tau蛋白病发病机制和进展。扩大项目范围的理由是:(i)临床
将血管病理与AD联系起来的证据;(ii)来自合作PI(和其他人)的新发现,
微血管病变和血脑屏障(BBB)功能障碍是tau蛋白病理学的关键驱动因素,
进展,(iii)最近获得了最先进的小鼠神经成像和质谱资源
能够翻译临床相关的脑成像以最终用于人类。新目标利用了
包括相同的充分表征的tau蛋白病小鼠模型(表达突变体人tau的P301 L小鼠),
资助的父项目。该模型表现出进行性微血管病变、tau蛋白病变和
与AD发病机制和进展相关的神经变性。我们将系统地调查
和脑病理的空间模式,并增加了对微血管功能障碍的关注,
相应的神经影像学检查我们计划实现一个目标来验证我们的假设,
微血管病变和神经元损失可以通过金属组学成像和脑的生物标志物染色来追踪。
血管健康我们的目的是研究tau蛋白病和
在表达突变型人P301 L tau的遗传性AD小鼠模型中的微血管病变。子目标1A:评价
通过分子标志物分析(SAA、CRP、VCAM-1、ICAM-1)和高分辨率
作为年龄的函数的tau蛋白病模型中的金属组成像质谱(hr-MIMS)脑映射,
疾病进展。子目标1B:将子目标1A的结果与定量免疫组织化学相关联
针对关键病理学终点(磷酸化tau蛋白病,p-tau/tau;
神经炎症,Iba-1;星形细胞增多,GFAP;神经元丢失)。我们将测试
微血管-BBB功能障碍是否会在解剖学上共定位,并在机制上与
小鼠模型中的tau蛋白病。
项目成果
期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Reduction of Phosphorylated Tau in Alzheimer's Disease Induced Pluripotent Stem Cell-Derived Neuro-Spheroids by Rho-Associated Coiled-Coil Kinase Inhibitor Fasudil
- DOI:10.3233/jad-230551
- 发表时间:2023-01-01
- 期刊:
- 影响因子:4
- 作者:Giunti,Elisa;Collu,Roberto;Xia,Weiming
- 通讯作者:Xia,Weiming
Laser induced breakdown spectroscopy for the rapid detection of SARS-CoV-2 immune response in plasma.
- DOI:10.1038/s41598-022-05509-z
- 发表时间:2022-01-31
- 期刊:
- 影响因子:4.6
- 作者:Berlo K;Xia W;Zwillich F;Gibbons E;Gaudiuso R;Ewusi-Annan E;Chiklis GR;Melikechi N
- 通讯作者:Melikechi N
Rule-Based Identification of Individuals with Mild Cognitive Impairment or Alzheimer's Disease Using Clinical Notes from the United States Veterans Affairs Healthcare System.
- DOI:10.1007/s40120-023-00540-2
- 发表时间:2023-12
- 期刊:
- 影响因子:3.7
- 作者:Aguilar, Byron J.;Miller, Donald;Jasuja, Guneet;Li, Xuyang;Shishova, Ekaterina;O'Connor, Maureen K.;Nguyen, Andrew;Morin, Peter;Berlowitz, Dan;Zhang, Raymond;Monfared, Amir Abbas Tahami;Zhang, Quanwu;Xia, Weiming
- 通讯作者:Xia, Weiming
Clinical Staging of Alzheimer's Disease: Concordance of Subjective and Objective Assessments in the Veteran's Affairs Healthcare System.
- DOI:10.1007/s40120-022-00379-z
- 发表时间:2022-09
- 期刊:
- 影响因子:3.7
- 作者:Morin, Peter;Li, Mingfei;Wang, Ying;Aguilar, Byron J.;Berlowitz, Dan;Tahami Monfared, Amir Abbas;Irizarry, Michael;Zhang, Quanwu;Xia, Weiming
- 通讯作者:Xia, Weiming
Longitudinal analysis of antibody decay in convalescent COVID-19 patients.
- DOI:10.1038/s41598-021-96171-4
- 发表时间:2021-08-18
- 期刊:
- 影响因子:4.6
- 作者:Xia W;Li M;Wang Y;Kazis LE;Berlo K;Melikechi N;Chiklis GR
- 通讯作者:Chiklis GR
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LEE E. GOLDSTEIN其他文献
LEE E. GOLDSTEIN的其他文献
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{{ truncateString('LEE E. GOLDSTEIN', 18)}}的其他基金
Impact of Toxic Metal Exposures in Novel Genetic Mouse Models of Late-Onset Alzheimer's Disease
有毒金属暴露对迟发性阿尔茨海默病的新型基因小鼠模型的影响
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10901030 - 财政年份:2023
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持久影响:用于研究创伤性脑损伤病理生理学的动态、完全自然的生物打印 3D 人体神经血管仿生模型
- 批准号:
10318506 - 财政年份:2021
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Lens β-Amyloid Biomarker for Early Detection of Preclinical Alzheimer's Disease in the Framingham Study
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10214179 - 财政年份:2021
- 资助金额:
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Lasting Impacts: Dynamic, Fully Natural Bioprinted 3D Human Neurovascular Biomimetic Model to Study Traumatic Brain Injury Pathophysiology
持久影响:用于研究创伤性脑损伤病理生理学的动态、完全自然的生物打印 3D 人体神经血管仿生模型
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TBI Identification and Monitoring Through Retinal Scanning
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10593933 - 财政年份:2020
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$ 41.25万 - 项目类别:
Big data and small molecules for Alzheimer's disease
阿尔茨海默病的大数据和小分子
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10168854 - 财政年份:2019
- 资助金额:
$ 41.25万 - 项目类别:
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