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MicroRNAs in CNS-derived extracellular microvesicles as peripheral blood biomarkers for Alzheimer disease

CNS 来源的细胞外微泡中的 MicroRNA 作为阿尔茨海默病的外周血生物标志物

基本信息

批准号：
10682404
负责人：
Min Shi
金额：
$ 67.53万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10682404
关键词：
Address Affect Alzheimer disease detection Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease risk Alzheimer’s disease biomarker Antibodies Astrocytes Binding Biological Assay Biological Markers Blood Blood Circulation Blood Tests Body Fluids Brain Brain region Cell physiology Cells Central Nervous System Cerebrospinal Fluid Cerebrospinal Fluid Proteins Characteristics Clinical Collection Complement Complex Cross-Sectional Studies Data Dementia Dementia with Lewy Bodies Development Diagnosis Diagnostic Differential Diagnosis Disease Disease Progression Exhibits Frontotemporal Dementia General Population Hippocampus Image Immunoassay Intervention Investigation Literature Measurement Measures Membrane Methods MicroRNAs Monitor Neural Cell Adhesion Molecule L1 Neurodegenerative Disorders Neurons Nucleic Acids Parkinson Disease Parkinson&apos s Dementia Pennsylvania Performance Pharmaceutical Preparations Pilot Projects Plasma Play Post-Transcriptional Regulation Process Production Prognosis Proteins Proteomics Reporting Research Research Personnel Reverse Transcriptase Polymerase Chain Reaction Role Sampling Sensitivity and Specificity Severity of illness Small RNA Societies Source Staging Surface Techniques Technology Testing Time Transcript Universities Untranslated RNA Validation Variant Vesicle Washington alpha synuclein biomarker panel biomarker validation blood-based biomarker body system candidate identification candidate marker cell type cohort design diagnostic accuracy differential expression disability exosome extracellular improved miRNA expression profiling microRNA biomarkers microvesicles mild cognitive impairment neuroimaging novel peripheral blood pre-clinical prodromal Alzheimer&apos s disease screening success tau Proteins treatment effect vesicle transport

项目摘要

Summary In this study we propose to address several major challenges in current Alzheimer disease (AD) biomarker research, specifically: 1) limited accessibility and high expense associated with neuroimaging measurements, 2) difficulties in developing antibody-based, quantitative protein assays for most novel candidates and significant variability among existing immunoassays, 3) invasive sampling inhibiting widespread use of CSF-based biomarkers, 4) low sensitivity/specificity and/or lack of validation in relatively large cohorts for blood-based markers, and, 5) detection of AD at early or even preclinical stages. To these ends we will target microRNAs packaged in central nervous system (CNS) derived extracellular microvesicles (EMVs) in blood plasma. microRNAs are a class of small, non-coding RNAs playing important roles in many cellular processes by post- transcriptional regulation of protein levels, and aberrant microRNA expression has become an emerging theme for a wide variety of diseases including AD and other neurodegenerative disorders. microRNAs found in body fluids can be routinely and reliably measured by well- established methods (e.g., RT-PCR), and data shows EMVs transport biomolecules between the CNS and peripheral blood and their cargo proteins and nucleic acids vary by cell of origin. Measurement of cargo proteins in such EMVs has shown particular promise in identifying blood- based biomarkers for AD and mild cognitive impairment (MCI, or prodromal AD). In a pilot R21 study, we employed global profiling of microRNAs in CNS-derived, relatively neuron-specific (L1CAM-positive) EMVs in plasma and identified many microRNA and other small RNA transcripts to be differentially expressed between AD and healthy controls, between AD and Parkinson disease, or between disease stages. Here, we aim to confirm and validate the identified candidates for AD/MCI diagnosis, differential diagnosis, and disease progression in several large, well-established cohorts, including Alzheimer's Disease Research Centers (ADRCs) affiliated with the University of Washington and University of Pennsylvania, and ADNI (Alzheimer's Disease Neuroimaging Initiative), with cross- sectional and longitudinal samples collected, along with extensive clinical characterization. In parallel, we will use global profiling methods to identify additional microRNA candidates in different CNS cell type- or neuronal subpopulation- specific EMVs in plasma. Finally, to improve early or pre-clinical diagnosis, we will evaluate potential microRNA biomarkers in a very early MCI cohort, subjects at elevated risk for AD. Our project design is geared towards the production of a panel of biomarkers that is more robust, repeatable, and clinically accessible than currently available.

概括在这项研究中，我们建议解决当前阿尔茨海默病 (AD) 的几个主要挑战生物标志物研究，特别是：1）与生物标志物研究相关的可及性有限且费用高昂神经影像测量，2) 开发基于抗体的定量蛋白质的困难大多数新颖候选物的测定以及现有免疫测定之间的显着差异，3) 侵入性采样抑制了基于脑脊液的生物标志物的广泛使用，4) 低灵敏度/特异性和/或缺乏在相对较大的群体中对基于血液的标记物的验证，以及，5) 检测 AD 处于早期甚至临床前阶段。为此，我们将靶向包装在中央血浆中神经系统（CNS）衍生的细胞外微泡（EMV）。微小RNA是一类小的非编码 RNA 在许多细胞过程中发挥重要作用蛋白质水平的转录调控和异常的 microRNA 表达已成为包括 AD 和其他神经退行性疾病在内的多种疾病的新兴主题失调。体液中发现的 microRNA 可以通过良好的方法进行常规、可靠的测量。已建立的方法（例如 RT-PCR），并且数据显示 EMV 在中枢神经系统和外周血及其货物蛋白和核酸因细胞来源而异。此类 EMV 中的货物蛋白测量在识别血液中显示出特别的前景。基于 AD 和轻度认知障碍（MCI，或前驱 AD）的生物标志物。在飞行员 R21 中研究中，我们对中枢神经系统衍生的、相对神经元特异性的 microRNA 进行了全局分析（L1CAM 阳性）血浆中的 EMV，并鉴定出许多 microRNA 和其他小 RNA 转录本 AD 和健康对照之间、AD 和帕金森病之间存在差异表达疾病或疾病阶段之间。在这里，我们的目标是确认和验证 AD/MCI 诊断、鉴别诊断的候选药物几个大型、成熟的队列中的诊断和疾病进展，包括华盛顿大学附属阿尔茨海默病研究中心 (ADRC) 和宾夕法尼亚大学和 ADNI（阿尔茨海默病神经影像计划），收集剖面和纵向样本，以及广泛的临床特征。在同时，我们将使用全局分析方法来识别不同的其他 microRNA 候选物血浆中 CNS 细胞类型或神经元亚群特异性 EMV。最后，要尽早改善或临床前诊断，我们将评估非常早期的 MCI 队列中潜在的 microRNA 生物标志物， AD 风险较高的受试者。我们的项目设计旨在生产面板比目前可用的生物标记物更稳健、可重复且临床可访问。