Biomarker Core

生物标志物核心

基本信息

批准号：
10667447
负责人：
Takahisa Kanekiyo
金额：
$ 46.37万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
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/10667447
关键词：
Acceleration Age-associated memory impairment Aging Alzheimer&apos 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 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 Proteomics Recording of previous events Research Risk Sampling Structural Models Structure Subjects Selections Symptoms Synapses System Time Translational Research Traumatic Brain Injury United States National Institutes of Health Universities Validation Visit Washington abeta deposition biomarker identification 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 neuropathology novel marker particle programs public database specific biomarkers synergism targeted biomarker tau Proteins tau-1

项目摘要

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.

项目摘要（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氏病（AD）和年龄相关的液体生物测量的认知能力下降，包括等离子体和血浆 U19计划中的项目和核心之间的脑脊液（CSF），特别关注APOE。给出 APOE基因型（ε2，ε3和ε4）已显示出影响较老的认知性能，我们假设载脂蛋白E（APOE）生化特性（量，脂质，聚集和聚集翻译后修饰）及其基因型会影响建立和新兴的生物流体标记物 AD的水平。我们将在2-3的时间范围内基于APOE基因型进行纵向生物标志物研究通过关注临床痴呆评级的变化（CDR），年龄（≥65岁）个体的年份（≥65岁）两次参观。路易。我们将利用NIH支持的大量生物测量的样本数量包括梅奥诊所衰老研究（MCSA）和阿尔茨海默氏病研究中心（ADRC）在内的计划在两个机构。在AIM 1中，我们将组织来自队列的可用数据集和流体生物测量。如果可用，我们还将将生物测量与事后大脑样本/神经病理学信息相结合通过神经病理核心（核心C）和外周血单核细胞产生诱导多能干细胞通过项目5和人IPSC模型核心（核心E）。在AIM 2中，我们计划建立与APOE相关的流体生物标志物进行临床痴呆进展。我们的目标是开发针对APOE的通过评估金额和潜在的翻译后的生物标志物，用于年龄相关的认知下降和AD 通过血浆和CSF样品中的LC-MS/MS方法修改APOE。脂质状态和 APOE颗粒的结构特性也将通过项目1和生物化学和结构进行探索建模核心（核心B）。在AIM 3中，我们旨在发现潜在的流体生物标志物以进行临床痴呆进展通过多摩斯核心（核心F）使用“ OMICS方法”。在AIM 4中，我们将产生一个流体生物标志物通过测量与新兴广告相关的数据集，以阐明APOE对临床痴呆进展的影响突触损伤和神经胶质激活以及注射/血管生物标志物的生物标志物。在AIM 5中，我们将支持流体生物标志物测量值，包括APOE测量和与AD相关的流体生物标志物根据请求，来自项目2-4和IPSC模型的鼠标模型的评估。一起，这个全面和创新的生物标志物核心将允许集成，基于系统的多学科研究通过专注于APOE同工型在疾病级联和与年龄相关的认知下降的级联。监视如何生物标志物随着时间的流逝而在渐近和早期症状阶段随着时间的流逝而变化。允许我们定义患者当前的疾病阶段，并预测更精确的临床进展方式。