ncRNAs in plasma EVs of AD patients and their discriminatory power as biomarkers

AD 患者血浆 EV 中的 ncRNA 及其作为生物标志物的区分能力

• 批准号: 10532000
• 负责人: RADOSVETA KOLDAMOVA
• 金额: $ 229.75万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10532000
• 关键词: 14q32; Affect; Agreement; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Area Under Curve; Autopsy; Binding; Biogenesis; Biological Assay; Biological Markers; Blood; Brain; Cerebrospinal Fluid; Clinic; Data Set; Dementia; Diagnosis; Diagnostic; Diagnostic tests; Disease; Disease Progression; Early Diagnosis; Epigenetic Process; Family; Genes; Genetic Transcription; Genomics; Genotype; Goals; Human; Human Activities; Imaging technology; Magnetic Resonance Imaging; Measures; Mediating; Messenger RNA; Methylation; Modeling; Molecular; Monitor; Mus; Nature; Neurons; Pathologic; Patients; Pattern; Performance; Phenotype; Plasma; Population; Positron-Emission Tomography; Predisposition; Property; Protein Isoforms; Proteins; Research; Risk; SNRPN; Sampling; Small Nucleolar RNA; Standardization; Technology; Testing; Therapeutic Effect; Transcript; UBE3A gene; Untranslated RNA; Validation; amyloid imaging; base; cohort; cost; detection sensitivity; diagnostic accuracy; diagnostic strategy; epigenomics; extracellular vesicles; hyperphosphorylated tau; imprint; machine learning algorithm; mind control; mouse model; neuroimaging marker; non-demented; prevent; promoter; prospective; protective effect; sample collection; tau Proteins; tau aggregation; tau-1

Alzheimer's disease is the most common and economically impactful form of dementia. Approaches based on cerebrospinal fluid and blood have been established to measure the levels of amyloid beta and hyperphosphorylated tau to facilitate early diagnosis of AD or to monitor the effects of therapeutics and progression of the disease. Plasma extracellular vesicles (EVs) and their cargo present an opportunity to isolate and profile molecules associated with human pathological conditions. We have recently discovered small nucleolar non-coding RNAs (snoRNAs) highly enriched in plasma EVs of AD patients compared to non-demented controls. We posit that tau aggregates irreversibly bind snoRNAs preventing them from performing their normal function resulting in a compensatory increase of their expression in AD brains. Our hypothesis is that the expression of certain SNORDs and their secretion in neuron derived EVs is increased with the progression of AD. Small non-coding nucleolar snoRNAs might represent ideal biomarkers, compared with proteins and/or mRNAs, because of the protective effect of plasma EV and the unprecedented sensitivity of detection by ddPCR technology – down to single transcripts. This proposal's primary goals are: 1) to test and validate the diagnostic accuracy of SNORD115 and SNORD116 ddPCR assays in human plasma; 2) to understand the nature of the associations between the abundance of particular SNORDs in AD plasma EVs, their expression level in brain, the disease state and progression, and if there is an association with APOE genotype; 3) to test for epigenetic mechanisms underlying the changes in abundance of SNORDs, and 4) using AD mouse models to reveal the effect of amyloid and tau aggregation on ISF, CSF and plasma EVs cargo. A better understanding of the underlying regulatory genomic, epigenomic, and cellular mechanisms responsible for the differences in the enrichment of SNORDs in plasma EVs of AD patients compared to Controls would help understand essential aspects of APOE mediated risk of AD and in establishing reliable diagnostic strategies.

阿尔茨海默病是最常见和经济上最具影响力的痴呆症形式。 已经建立了基于脑脊液和血液的方法来测量水平 淀粉样蛋白β和过度磷酸化的tau蛋白，以促进AD的早期诊断或监测 治疗效果和疾病进展。血浆细胞外囊泡（EV）和 他们的货物提供了一个机会，分离和分析与人类相关的分子， 病理条件。我们最近发现了小的核仁非编码RNA 与非痴呆对照相比，在AD患者的血浆EV中高度富集的RNA（snoRNA）。 我们认为，tau聚集体不可逆地结合snoRNA，阻止它们执行其功能。 正常功能，导致其在AD脑中表达的代偿性增加。我们 一种假设是，某些SNORD的表达及其在神经元衍生的EV中的分泌是 随着AD的进展而增加。小的非编码核仁snoRNA可能代表理想的 与蛋白质和/或mRNA相比，由于血浆的保护作用， EV和ddPCR技术前所未有的检测灵敏度-低至单个 成绩单 该方案的主要目标是：1）测试和验证SNORD 115的诊断准确性 和SNORD 116 ddPCR检测; 2）了解相关性的性质 AD血浆EV中特定SNORD的丰度，它们在脑中的表达水平， 疾病状态和进展，以及是否与APOE基因型相关; 3）检测 SNORD丰度变化的表观遗传机制，以及4）使用AD 揭示淀粉样蛋白和tau聚集对ISF、CSF和血浆EV的影响的小鼠模型 货物.更好地了解潜在的调控基因组，表观基因组和细胞 负责AD血浆EV中SNORD富集差异的机制 与对照组相比，患者将有助于了解APOE介导风险的基本方面 以及建立可靠的诊断策略。