Molecular Markers of Cerebrovascular Pathologies in Alzheimer's Disease and Related Dementias

阿尔茨海默病和相关痴呆症脑血管病理学的分子标志物

基本信息

批准号：
10806855
负责人：
Denes V. Agoston
金额：
$ 68.44万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-25 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10806855
关键词：
3xTg-AD mouse Abeta clearance Acceleration Address Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Amyloid beta-Protein Animal Model Animals Architecture Biological Markers Blood Blood Vessels Blood flow Brain Cells Cerebrovascular Circulation Cerebrovascular system Cerebrum Clinical Clinical Research DNA Sequence Alteration Data Deposition Disease Disease Marker Disease Progression Early Diagnosis Early identification Endothelial Cells Endothelium Equipment and supply inventories Evolution Exhibits Female Functional disorder Future Gene Expression Genes Genome Genomics Glial Fibrillary Acidic Protein Goals Growth HMGB1 gene Human IL6 gene Image Impaired cognition Inflammation Inflammatory Knock-in Knowledge Linear Regressions Link Literature Longevity MMP9 gene Magnetic Resonance Imaging Measures Methods Modeling Modification Monitor Morphology Mus Nerve Degeneration Neurofilament-L Neurons Onset of illness Outcome Paint Pathology Patients Pattern Perfusion Phosphorylation Physiology Proteins Recovery Reporting Research Research Personnel Role Senile Plaques Severity of illness Sex Differences Stress Structure Symptoms System TREM2 gene Tauopathies Testing Time Translating Treatment Efficacy VWF gene Variant Vascular Diseases Vascular Endothelial Growth Factors Wild Type Mouse abeta accumulation abeta deposition biomarker panel biomarker signature blood-based biomarker cerebrovascular cerebrovascular pathology clinically relevant defined contribution density experimental study genomic biomarker genomic profiles genomic signature human model human subject innovation male molecular marker mouse model novel pre-clinical preclinical study predictive marker predictive modeling protein biomarkers risk variant sex single nucleus RNA-sequencing tau Proteins tau aggregation temporal measurement timeline transcriptomics two photon microscopy two-photon vascular abnormality

项目摘要

Summary Project Clinical and preclinical studies have demonstrated perturbations to the cerebrovascular network in Alzheimer’s Disease (AD) in sex-specific manner. Altered blood flow, cerebrovascular reactivity, and vessel topologies are all hallmarks of progressing AD in animal models and in human subjects. Blood-borne protein biomarkers have reported altered profiles in humans and mouse models of AD. AD research has predominately focused on neuronal, inflammatory and glial markers of disease progression. At the present time there are no studies that directly relate AD-induced changes in angioarchitecture to blood-borne protein biomarkers of endothelial stress and vascular dysfunction. Similarly, there are no studies linking blood borne protein biomarkers to vessel genomics, specifically targeting endothelial cell genes. This is a critical gap with significant clinical value because several studies suggest that vascular abnormalities precede AD onset. Therefore, blood-borne protein biomarkers could be used to predict likelihood of vulnerability to AD, disease onset and progression. This gap in knowledge will be addressed by this proposal, with the goal of describing the temporal evolution and relationships between damaged vascular networks and blood-based protein biomarkers and vascular genes. We have previously reported in AD mouse models there is an altered vascular density and complexity with increasing age. Sex differences have also been poorly studied within the context of vascular biomarkers, a gap we will also directly address in this proposal. Four interrelated but not interdependent Aims will elucidate the relationship between vessel genomics, cerebrovascular structure and function modifications and blood-borne protein biomarkers of endothelial and vascular functions. Aim 1 will examine in fine detail the timeline of vascular function structural changes over the lifetime (4, 12, >18mo) in 5xFAD mice of both sexes. Known risk variants will be added to clarify the effects of amyloid β seeding. The blood-based biomarkers will focus on proteins of endothelial stress, vascular damage and recovery (VEGF, vWF, Claudin-5, etc), glial (GFAP), inflammation (IL-1b, TNFa, HMGB1, IL6, MMP9) and neuronal damage and neurodegeneration (NF-L, Tau and its various phosphorylated forms and Abeta40 and 42). We believe that a panel of blood-borne biomarkers will accurately reflect the underlying cerebrovascular abnormalities with increasing age. Aim 2 will utilize the 3xTg AD mouse that has early amyloid β followed by tau deposition and 3xTg mice with the addition of risk variants. Aims 1-3 will utilize the identical methods biomarkers, genomes and structure/function assessments. Aim 4 will model all the findings to identify a unique biomarker set that has predictive capabilities for AD onset. The proposed project will provide technical and conceptual innovations through using a unique combinatory approach to establish direct relationships between blood-borne biomarkers and vascular function and topology, as well as genomic markers from the same animals of both sexes using PWI MRI, 2-photon microscopy, vessel painting, state-of-the-art spatial transcriptomics and single-nucleus RNA-seq and blood-borne protein biomarkers. Such innovative biomarkers would enable early identification of patients with elevated risk for AD, prediction of AD onset and severity, and objective monitoring treatment efficacy, our long-term research objectives.

项目总结临床和临床前研究已证明对脑血管网络的干扰阿尔茨海默氏病（AD）以性别特异性方式改变。拓扑结构都是动物模型和人类受试者中 AD 进展的标志。生物标志物报告了 AD 研究中人类和小鼠模型的特征发生了改变。目前主要关注疾病进展的神经元、炎症和神经胶质标记物。目前还没有研究将 AD 引起的血管结构变化与血源性蛋白质直接联系起来同样，没有研究将内皮应激和血管功能障碍联系起来。血管基因组学的蛋白质生物标志物，特别是针对内皮细胞基因，这是一个关键的差距。具有重要的临床价值，因为多项研究表明血管异常先于 AD 发病。因此，血源性蛋白质生物标志物可用于预测患 AD、疾病的可能性该提案将解决这一知识差距，目的是描述。受损血管网络和血液蛋白之间的时间演变和关系我们之前在 AD 小鼠模型中报道过生物标志物和血管基因。血管密度和复杂性随年龄增长的差异也得到了很少的研究。在血管生物标志物的背景下，我们也将在本提案中直接解决四个相互关联但存在的差距。不相互依赖目标将阐明血管基因组学、脑血管结构之间的关系目标 1：内皮和血管功能的功能修饰和血源性蛋白质生物标志物。将详细检查一生中血管功能结构变化的时间表（4、12、>18 个月）在两种性别的 5xFAD 小鼠中添加已知的风险变异以阐明淀粉样蛋白 β 接种的影响。基于血液的生物标志物将重点关注内皮应激、血管损伤和恢复的蛋白质（VEGF、vWF、Claudin-5 等）、胶质细胞 (GFAP)、炎症（IL-1b、TNFa、HMGB1、IL6、MMP9）和神经元损伤和神经变性（NF-L、Tau 及其各种磷酸化形式以及 Abeta40 和 42）。相信一组血源性生物标志物将准确反映潜在的脑血管目标 2 将利用具有早期淀粉样蛋白 β 的 3xTg AD 小鼠。 tau 沉积和添加风险变异的 3xTg 小鼠将使用相同的方法。目标 4 将对生物标志物、基因组和结构/功能评估进行建模，以确定该项目将提供具有 AD 发病预测能力的独特生物标志物集。通过使用独特的组合方法建立直接关系进行概念创新血源性生物标志物与血管功能和拓扑结构之间的关系，以及来自血液的基因组标志物之间的关系使用 PWI MRI、双光子显微镜、血管绘画、最先进的空间技术对相同的两性动物进行研究转录组学、单核 RNA 测序和血源性蛋白质生物标志物。生物标记物将能够及早识别 AD 风险升高的患者、预测 AD 发病和严重程度，并客观监测治疗效果，是我们的长期研究目标。