Biomarker Core

生物标志物核心

基本信息

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
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/10407939
关键词：
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 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

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病 (AD) 和液体生物样本（包括血浆和血浆）中与年龄相关的认知能力下降 U19 计划中的项目和核心中的脑脊液 (CSF)，特别关注 APOE。 APOE 基因型（ε2、ε3 和 ε4）已被证明会影响老年人的认知表现，我们培养载脂蛋白 E (apoE) 生化特性（数量、脂化、聚集和翻译后修饰）及其基因型影响已建立和新兴的生物流体标记我们将在 2-3 的时间跨度内进行基于 APOE 基因型的纵向生物标志物研究。重点关注老年人（≥65岁）临床痴呆评级（CDR）的变化在梅奥诊所和圣路易斯华盛顿大学医学院建立的队列的两次访问之间路易斯，我们将利用 NIH 支持的大量生物样本。项目包括梅奥诊所衰老研究 (MCSA) 和阿尔茨海默病研究中心 (ADRC) 在目标 1 中，我们将组织来自队列的可用数据集和液体生物样本。如果可用，我们还将生物样本与死后脑样本/神经病理学信息相结合通过神经病理核心（Core C）与外周血单核细胞产生诱导在目标 2 中，我们计划通过项目 5 和人类 iPSC 模型核心（核心 E）开发多能干细胞。建立用于临床痴呆进展的 apoE 相关液体生物标志物我们的目标是开发 apoE 靶向的。通过评估数量和潜在的翻译后，与年龄相关的认知能力下降和AD的生物标志物通过 LC-MS/MS 方法对血浆和脑脊液样本中的 apoE 进行修饰。 apoE 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。在目标 4 中，我们将通过多组学核心（核心 F）使用“组学方法”生成流体生物标记物。通过测量新出现的 AD 相关数据来阐明 APOE 对临床痴呆进展的影响在目标 5 中，我们研究了突触损伤和神经胶质激活的生物标志物，以及炎症/血管生物标志物。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对项目 2-4 的小鼠模型和项目 5 的 iPSC 模型进行评估。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 疾病级联中的 apoE 异构体和年龄相关的认知能力下降来监测。在表型良好的人群中，生物标志物在无症状和早期症状阶段随时间变化可能使我们能够定义患者当前的疾病阶段并更准确地预测临床进展方式。