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

• 批准号: 10463539
• 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
• 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/10463539
• 关键词: Address; Affect; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Antibodies; Astrocytes; Biological Assay; Biological Markers; Blood; Blood Circulation; Blood Tests; Body Fluids; Brain; Brain region; Cell physiology; Cells; 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 (Brain); Image; Immunoassay; Intervention; Investigation; Literature; Measurement; Measures; Membrane; Methods; MicroRNAs; Monitor; Neural Cell Adhesion Molecule L1; Neuraxis; Neurodegenerative Disorders; Neurons; Nucleic Acids; Parkinson Disease; Parkinson' 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; Technology; Testing; Time; Transcript; Universities; Untranslated RNA; Validation; Variant; Vesicle; Washington; alpha synuclein; base; biomarker panel; blood-based biomarker; body system; candidate marker; cell type; clinical diagnosis; 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' s disease; screening; success; tau Proteins; treatment effect

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.

总结 在这项研究中，我们提出了解决目前阿尔茨海默病（AD）的几个主要挑战， 生物标志物研究，特别是：1）有限的可及性和高费用与 神经影像学测量，2）开发基于抗体的定量蛋白质的困难 大多数新候选物的测定和现有免疫测定之间的显著变异性，3） 侵入性采样抑制了基于CSF的生物标志物的广泛使用，4）低灵敏度/特异性 和/或在相对大的群组中缺乏对基于血液的标志物的验证，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 神经系统（CNS）来源的细胞外微泡（EMV）。微小rna是 一类小的非编码RNA，在许多细胞过程中起重要作用， 蛋白质水平的转录调控，以及异常的microRNA表达已经成为一个重要的研究领域。 包括AD和其他神经退行性疾病在内的各种疾病的新兴主题 紊乱在体液中发现的microRNA可以通过良好的 已建立的方法（例如，RT-PCR），数据显示EMV在细胞之间转运生物分子。 CNS和外周血及其货物蛋白和核酸因细胞来源而异。 在这种EMV中的货物蛋白的测量已经显示出在鉴定血液中的特别希望。 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 在这项研究中，我们采用了CNS衍生的相对神经元特异性的microRNA的全局分析。 （L1 CAM阳性）血浆中的EMV，并鉴定了许多microRNA和其他小RNA转录物 在AD和健康对照之间，在AD和帕金森之间， 疾病或疾病阶段之间。 在这里，我们的目标是确认和验证已确定的候选人AD/MCI诊断，鉴别诊断， 诊断和疾病进展，在几个大型的，完善的队列，包括 阿尔茨海默病研究中心（ADRC）附属于华盛顿大学， 宾夕法尼亚大学，和ADNI（阿尔茨海默病神经影像学倡议），与交叉- 收集的截面和纵向样本，沿着广泛的临床表征。在 与此同时，我们将使用全局分析方法来识别不同基因组中的其他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，我们将在非常早期的MCI队列中评估潜在的microRNA生物标志物， AD风险升高的受试者。我们的项目设计是面向生产的面板， 这些生物标志物比目前可用的生物标志物更稳健、可重复和临床上可获得。