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.

阿尔茨海默氏病是最常见且对经济影响最大的痴呆症形式。 已经建立了基于脑脊液和血液的方法来测量其水平 β 淀粉样蛋白和过度磷酸化的 tau 蛋白，以促进 AD 的早期诊断或监测 治疗效果和疾病进展。 他们的货物提供了分离和分析与人类相关的分子的机会 我们最近发现了小的核仁非编码RNA。 与非痴呆对照相比，AD 患者血浆 EV 中高度富集 snoRNA（snoRNA）。 我们假设 tau 聚集体不可逆地结合 snoRNA，从而阻止它们发挥作用 正常功能导致它们在 AD 大脑中的表达代偿性增加。 假设某些 SNORD 的表达及其在神经元来源的 EV 中的分泌是 随着 AD 进展而增加。小非编码核仁 snoRNA 可能是理想的代表。 与蛋白质和/或 mRNA 相比，由于血浆的保护作用，生物标志物 EV 和 ddPCR 技术前所未有的检测灵敏度 – 低至单倍 成绩单。 该提案的主要目标是：1）测试和验证 SNORD115 的诊断准确性 和人血浆中的 SNORD116 ddPCR 测定；2) 了解关联的性质； AD 血浆 EV 中特定 SNORD 的丰度与它们在大脑中的表达水平之间的关系， 疾病状态和进展，以及是否与 APOE 基因型相关 3) 进行测试； 了解 SNORD 丰度变化背后的表观遗传机制，以及 4) 使用 AD 小鼠模型揭示淀粉样蛋白和 tau 蛋白聚集对 ISF、CSF 和血浆 EV 的影响 更好地了解潜在的调控基因组、表观基因组和细胞。 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 AD 并建立可靠的诊断策略。