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.

阿尔茨海默氏病是痴呆症的最常见和经济上有影响力的形式。 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和高磷酸化的TAU，以促进AD的早期诊断或监测 治疗和疾病进展的影响。血浆细胞外蔬菜（EV）和 他们的货物提供了与人类相关的分离和剖面分子的机会 病理状况。我们最近发现了小核仁非编码RNA （SNORNA）与非痴呆对照相比，高度富含AD患者的血浆EV。 我们指出，tau不可逆转地绑定了snornas，以防止他们执行他们 正常功能导致其在AD大脑中表达的补偿性增加。我们的 假设是某些snord的表达及其在神经元中的分泌是 随着AD的发展而增加。小型非编码核sin词可能代表理想 与蛋白质和/或mRNA相比，生物标志物的保护作用 EV和DDPCR技术对检测的前所未有的敏感性 - 直到单一 成绩单。 该提议的主要目标是：1）测试和验证SNORD115的诊断准确性 和SNORD116 DDPCR在人血浆中的测定； 2）了解协会的本质 在AD等离子体EV中特定的SNORD的抽象（它们在大脑中的表达水平）之间 疾病状态和进展，如果与APOE基因型有关联； 3）测试 用于表观遗传机制，其基础的抽象变化以及4）使用AD 小鼠模型揭示了淀粉样蛋白和tau聚集对ISF，CSF和等离子体EV的影响 货物。更好地理解潜在的调节基因组，表观基因组和细胞 负责AD血浆中的SNORD浓度差异的机制 与对照组相比，患者将有助于理解APOE介导的风险的基本方面 广告并建立可靠的诊断策略。