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.

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

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

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

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

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

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