Big data and small molecules for Alzheimer's disease

摘要 此管理补充应用程序的目标是使用我们的高分辨率金属组学成像 脑微血管损伤与发病机制相关的脑电地形图研究 和阿尔茨海默病(AD)的进展。具体地说，我们建议进行表型分析 在我们的NIA资助的RF1项目(《阿尔茨海默病的大数据和小分子》1RF1AG063913-- 01)通过应用创新的、最先进的质谱学技术来表征大脑表型 终端。由RF1资助的父项目旨在大量确定特定的ACEI+STAT药物 国家数据库和测试ACEI+STAT联合治疗抑制病理表型的疗效 在多动症小鼠模型中。在本补充方案中，我们将在同一小鼠中添加表型分析 模特。我们将研究脑微血管损伤和相应的成像和生物标记物 颈椎病的发病机制和进展。扩大项目范围的理由是：(I)临床 将血管病理与阿尔茨海默病联系起来的证据；(Ii)合作的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蛋白病理和 进展，(3)最近获得最先进的小鼠神经成像和质谱学资源 这使得与临床相关的脑成像能够被翻译出来，最终用于人类。新的目标利用 相同的特征良好的直肠结肠炎小鼠模型(表达突变的人tau的P301L小鼠)包括在 受资助的父项目。该模型表现为进行性微血管病变、节段性病变和 神经退行性变与AD的发病和进展有关。我们将系统地研究时间 和脑病理的空间模式，并增加对微血管功能障碍的关注，以及与 相应的神经成像。我们计划实现一个目标来验证我们的假设，即直立面疗法， 微血管病变和神经元丢失可以通过金属组学成像和脑内生物标记物的染色来追踪 血管健康。我们的目标是研究直立位和直立位之间的时间、解剖和机械联系。 表达突变人P301L tau的遗传性阿尔茨海默病小鼠的微血管病变。次级目标1：评价 分子标志物(SAA、CRP、VCAM-1、ICAM-1)和高分辨率检测脑微血管病变 金属组成像质谱仪(hr-MIMS)在直肠畸形模型中随年龄和年龄的变化而进行的脑成像 疾病的发展。次级目标1B：将次级目标1A的结果与定量免疫组织化学相关联 针对关键病理终点(磷酸化tau病，p-tau/tau； 神经炎症，Iba-1；星形胶质细胞增多症，GFAP；神经元丢失)与肌张力障碍的进展有关。我们将测试 微血管-血脑屏障功能障碍是否会在解剖学上共存，并在力学上与高血压的进展有关 在小鼠模型中出现牵牛症。

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.