Biomarker Core

生物标志物核心

• 批准号: 10407939
• 负责人: Takahisa Kanekiyo
• 金额: $ 46.71万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10407939
• 关键词: Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer’s disease biomarker; Amyloid beta-42; Animals; Apolipoprotein E; Autopsy; Biochemical; Biochemistry; Bioinformatics; Biological; Biological Assay; Biological Markers; Biological Specimen Banks; Biology; Biometry; Blood Vessels; Brain; Brain Neoplasms; Cerebrospinal Fluid; Classification; Clinic; Clinical; Collaborations; Communities; Data; Data Set; Dementia; Dependence; Deposition; Diagnosis; Disease; Disease Progression; E protein; Early Diagnosis; Elderly; Genotype; Goals; Human; Individual; Inflammation; Infrastructure; Institution; Link; Lipids; Liquid substance; Longitudinal cohort; Magnetic Resonance Imaging; Measurement; Measures; Modeling; Monitor; Mus; Nerve Degeneration; Onset of illness; Pathogenicity; Pathologic; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Persons; Phase; Phenotype; Plasma; Positron-Emission Tomography; Post-Translational Protein Processing; Prevention; Process; Property; Protein Isoforms; Proteins; Proteomics; Recording of previous events; Research; Risk; S-nitro-N-acetylpenicillamine; Sampling; Structural Models; Structure; Symptoms; Synapses; System; Time; Translational Research; Traumatic Brain Injury; United States National Institutes of Health; Universities; Validation; Visit; Washington; abeta deposition; base; cell type; clinical predictors; cognitive performance; cohort; data management; design; disease classification; fluorodeoxyglucose positron emission tomography; glial activation; human old age (65+); induced pluripotent stem cell; innovation; lipidomics; medical schools; mouse model; multidisciplinary; multiple omics; neuroimaging; novel marker; particle; programs; public database; specific biomarkers; targeted biomarker; tau Proteins; tau-1; vascular inflammation

PROJECT SUMMARY (APOE U19 Core D: Biomarker Core) The overall goal of the Biomarker Core (Core D) is to conduct and support the biomarker assessments for Alzheimer’s disease (AD) and age-related cognitive decline in fluid biospecimens including plasma and cerebrospinal fluid (CSF) among Projects and Cores in the U19 program with a specific focus on APOE. Given that APOE genotype (ε2, ε3 and ε4) has been shown to impact cognitive performances in the elderly, we hypothesize that apolipoprotein E (apoE) biochemical property (amount, lipidation, aggregation and post-translational modification) as well as its genotypes influence established and emerging biofluid-marker levels for AD. We will perform longitudinal biomarker studies based on APOE genotype over a time span of 2-3 years in elderly (≥65 years old) individuals by focusing on the change of Clinical Dementia Rating (CDR) between two visits in established cohorts from Mayo Clinic and Washington University School of Medicine in St. Louis. We will take advantage of the large sample numbers of biospecimens banked in the NIH-supported programs including Mayo Clinic Study of Aging (MCSA) and the Alzheimer's Disease Research Centers (ADRC) at both institutions. In Aim 1, we will organize the available dataset and fluid biospecimens from the cohorts. If available, we will also integrate the biospecimens with postmortem brain samples/neuropathological information through the Neuropathological Core (Core C) and peripheral blood mononuclear cells to generate induce pluripotent stem cells through Project 5 and the Human iPSC Models Core (Core E). In Aim 2, we plan to establish apoE-related fluid biomarkers for clinical dementia progression. We aim to develop apoE-targeted biomarkers for age-related cognitive decline and AD by assessing amounts and potential post-translational modification of apoE through LC-MS/MS approaches in plasma and CSF samples. Lipidation status and structural properties of apoE particles will also be explored through Project 1 and the Biochemistry and Structural Modeling Core (Core B). In Aim 3, we aim to uncover potential fluid biomarkers for clinical dementia progression using an ‘Omics approach through the Multi-Omics Core (Core F). In Aim 4, we will generate a fluid biomarker dataset to elucidate the effects of APOE on clinical dementia progression by measuring emerging AD-related biomarkers for synaptic damage and glial activation, as well as inflammation/vascular biomarkers. In Aim 5, we will support fluid biomarker measurements including apoE measurements and AD-related fluid biomarker assessments in mouse models from Projects 2-4 and iPSC models from Project 5 upon requests. Together, this comprehensive and innovative Biomarker Core will allow for integrated, systems-based, multidisciplinary studies by focusing on apoE isoforms in the disease cascade for AD and age-related cognitive decline. Monitoring how biomarkers change over time in asymptomatic and early symptomatic stages in well-phenotyped cohorts might allow us to define the current disease phases of patients and predict clinical progression in a more precise manner.

项目总结（APOE U19核心D：生物标志物核心） 生物标志物核心（核心D）的总体目标是进行和支持生物标志物评估， 阿尔茨海默病（AD）和年龄相关的认知下降的液体生物标本，包括血浆和 在U19项目的项目和核心中，特别关注APOE。给定 APOE基因型（ε2，ε3和ε4）已被证明影响老年人的认知能力，我们 假设载脂蛋白E（apoE）生化性质（量、脂化、聚集和 翻译后修饰）以及其基因型影响已建立和新兴的生物流体标记物 AD的水平。我们将根据APOE基因型在2-3年的时间跨度内进行纵向生物标志物研究。 通过关注临床痴呆评分（CDR）的变化， 在来自马约诊所和位于圣路易斯的华盛顿大学医学院的既定队列中， Louis.我们将利用NIH支持的生物样本库中的大量样本， 包括马约诊所衰老研究（MCSA）和阿尔茨海默病研究中心（ADRC）在内的项目 在这两个机构。在目标1中，我们将组织队列中的可用数据集和液体生物标本。如果 我们还将把生物标本与死后大脑样本/神经病理学信息结合起来， 通过神经病理核心（Core C）和外周血单个核细胞产生诱导 多能干细胞通过项目5和人类iPSC模型核心（核心E）。在目标2中，我们计划 建立临床痴呆进展的apoE相关液体生物标志物。我们的目标是开发针对apoE的 通过评估与年龄相关的认知衰退和AD的量和潜在的翻译后 通过LC-MS/MS方法在血浆和CSF样品中修饰apoE。脂质化状态和 载脂蛋白E颗粒的结构特性也将通过项目1和生物化学和结构 建模核心（核心B）。在目标3中，我们的目标是发现临床痴呆进展的潜在液体生物标志物 通过Multi-Omics Core（Core F）使用组学方法。在目标4中，我们将生成流体生物标志物 数据集，通过测量新出现的AD相关性，阐明APOE对临床痴呆进展的影响 突触损伤和神经胶质活化的生物标志物，以及炎症/血管生物标志物。目标5：我们 将支持液体生物标志物测量，包括apoE测量和AD相关液体生物标志物 根据要求，在项目2-4的小鼠模型和项目5的iPSC模型中进行评估。在一起，这 全面和创新的生物标志物核心将允许综合的，基于系统的，多学科的研究 通过关注AD和年龄相关的认知能力下降的疾病级联中的apoE亚型。如何监测 在表型良好的队列中，无症状和早期症状阶段生物标志物随时间的变化可能 使我们能够更精确地定义患者的当前疾病阶段并预测临床进展 方式