Big data and small molecules for Alzheimer's disease

阿尔茨海默病的大数据和小分子

• 批准号: 10217833
• 负责人: LEE E. GOLDSTEIN
• 金额: $ 41.25万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10217833
• 关键词: Administrative Supplement; Age; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; Anatomy; Astrocytosis; Big Data; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Mapping; Brain Pathology; Brain imaging; C-reactive protein; Chromosome 17; Clinical; Combined Modality Therapy; Databases; Disease Progression; Exhibits; FTD with parkinsonism; Functional disorder; Funding; Genetic; Glial Fibrillary Acidic Protein; Goals; Harvest; Health; Human; Image; Impairment; Intercellular adhesion molecule 1; Interleukin-6; Intervention; Knowledge; Link; Mass Spectrum Analysis; Methods; Microvascular Dysfunction; Modeling; Mus; Nerve Degeneration; Neurofibrillary Tangles; Onset of illness; Pathogenesis; Pathologic; Pathology; Pattern; Pharmaceutical Preparations; Pharmacology; Phenotype; Plasma; Reporting; Resolution; Resources; Serum amyloid A protein; Stains; Tauopathies; Techniques; Technology; Testing; Transgenic Mice; Treatment Efficacy; United States Department of Veterans Affairs; Vascular Cell Adhesion Molecule-1; Veterans; Work; base; cerebrovascular health; clinical translation; clinically relevant; clinically translatable; data warehouse; design; efficacy testing; imaging biomarker; innovation; molecular marker; mouse model; mutant; neuroimaging; neuroinflammation; neuron loss; novel therapeutics; parent project; pre-clinical; small molecule; tau Proteins; tau mutation; tau-1

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.

抽象的 此行政补充应用的目的是使用我们的高分辨率金属成像 质谱（HR-MIMS）用于与发病机理相关的微血管障碍的脑图 和阿尔茨海默氏病（AD）的进展。特别是，我们建议进行进行表型分析 在我们的NIA资助的RF1项目（“阿尔茨海默氏病的大数据和小分子）” 1RF1AG063913- 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RF1父项目旨在识别大型ACEI+Stat药物 国家数据库并测试ACEI+Stat组合疗法抑制病理表型的效率 在Tauopathy鼠标模型中。在此补充建议中，我们将在同一鼠标中添加表型分析 模型。我们将研究脑微血管障碍以及相应的成像和与生物标志物相关的生物标志物 陶氏病的发病机理和进展。扩大项目范围的基本原理由：（i）临床 将血管病理与AD联系起来的证据； （ii）合作的PIS（和其他）的新发现 作为tau蛋白质病理学的关键驱动因素和微脑病和血脑屏障（BBB）功能障碍 进展，（iii）最新的最新小鼠神经影像学和质谱资源的收购 这使得临床上与临床相关的大脑成像的翻译最终可以在人类中使用。新目标的利用 包括在相同特征良好的tauopathy小鼠模型（表达突变人tau的P301L小鼠）中 资助的家长项目。该模型表现出进行性的微举行病，tauopathy和 与AD发病机理和进展有关的神经变性。我们将系统地研究临时性 和大脑病理的空间模式，并增加了对微血管功能障碍以及与 相应的神经影像学。我们计划实现一个目标，以检验我们的假设，即tauopathy， 可以通过金属成像和大脑生物标志物的染色来跟踪微举足病和神经元丧失 血管健康。我们旨在调查tauopathy和 表达突变体P301L tau的遗传AD小鼠模型中的微举足病。 Sub-aim 1A：评估 分子标记物分析（SAA，CRP，VCAM-1，ICAM-1）和高分辨率的脑微举行 金属成像质谱法（HR-MIMS）大脑映射在tauopathy模型中，随着年龄和年龄的函数 疾病进展。 Sub-aim 1b：将子-AIM 1A的结果与定量免疫组织化学相关联 分析靶向关键病理终点的收获大脑（磷酸化的tauopathy，p-tau/tau； 神经炎症，IBA-1；星形细胞增多症，GFAP；神经元丧失）与陶氏病的进展有关。我们将测试 微血管BBB功能障碍是否会在解剖上共定位并机械地与 小鼠模型中的tauopathy。

项目成果

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: JOURNAL OF ALZHEIMERS DISEASE
• 影响因子: 4
• 作者: Giunti，Elisa;Collu，Roberto;Xia，Weiming
• 通讯作者: Xia，Weiming

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: NEUROLOGY AND THERAPY
• 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

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: Scientific reports
• 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

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: Scientific reports
• 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

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: NEUROLOGY AND THERAPY
• 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