tRNA-derived RNA Fragments, A New Regulator for Alzheimer's Disease

tRNA 衍生的 RNA 片段，阿尔茨海默病的新调节因子

• 批准号: 10055621
• 负责人: Xiaoyong Bao
• 金额: $ 43.45万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10055621
• 关键词: Affect; Age; Alzheimer' s Disease; Alzheimer' s disease patient; Bioinformatics; Biological; Biological Assay; Biological Process; Blood; Cerebrospinal Fluid; Clinical; Code; Collaborations; Communicable Diseases; Comprehension; Data; Databases; Dementia; Dependence; Deposition; Development; Disease; Disease Marker; Disease Progression; Early Diagnosis; Elderly; Etiology; Expression Profiling; Eye; Family; Gender; Gene Expression Regulation; Genes; Genetic Transcription; Genome; Genomics; Goals; Heavy Metals; High-Throughput Nucleotide Sequencing; Hippocampus (Brain); Human Genome; Inflammation; Instruction; Interdisciplinary Study; Knowledge; Malignant Neoplasms; Memory Disorders; Messenger RNA; MicroRNAs; Microglia; Molecular; Monitor; Neurodegenerative Disorders; Neurons; Onset of illness; Outcome; Pathogenesis; Pathway interactions; Patients; Pattern; Physician Executives; Play; Presenile Alzheimer Dementia; Prevention; Process; Property; Proteins; RNA; RNA Sequences; Race; Reporting; Research; Risk Factors; Role; Sample Size; Sampling; Severities; Severity of illness; Specificity; Stimulus; Stress; Testing; Therapeutic; Tissues; Transcriptional Activation; Transfer RNA; Untranslated RNA; Virus; Virus Diseases; Work; base; biomarker identification; brain tissue; combat; diagnostic biomarker; differential expression; disease phenotype; disorder prevention; experience; human disease; human very old age (85+); insight; member; method development; novel; novel diagnostics; patient population; pollutant; programs; specific biomarkers; statistics; therapeutic target; tissue resource; tool; transcription factor

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is the most common neurodegenerative disorder, with low specificity of clinical tests (<70%), due to its pathophysiological process which is largely unknown. Genomic comprehension has been significantly advanced due to the discovery of noncoding RNAs (ncRNAs) as the major product of the transcribed genome. Although recent studies suggest that ncRNAs, especially microRNAs (miRNAs) and long ncRNAs (lncRNAs), are implicated in AD development, only a limited number of miRNAs/lncRNAs- dysregulated pathways were identified, some of which are of dubious relevance to the onset, progression, and pathogenesis of AD. In addition, miRNAs/lncRNAs known to be altered in AD are not always AD-specific, as such changes also occur in other neurodegenerative diseases. Furthermore, the functions of many ncRNAs in AD, especially of emerging ncRNAs, are not known. Our recent experimental data demonstrated that the expression profile of tRNA-derived RNA fragments (tRFs), a recently identified family of ncRNAs, was significantly impacted in AD. Some changes in tRFs were much more significant than changes in miRNAs, and these changes had a pattern of age- and/or stage-dependence in AD patients. Here, we hypothesize that tRFs are key contributors to AD progression and pathogenesis. We will determine tRF signatures associated with AD severity and early-onset AD (Aim 1). We will also identify the targets of aberrant tRFs in AD (Aim 2). Our research experience in the discovery of tRF induction and functions in viral infection and by environmental heavy metal pollutants has provided us with the expertise and tools needed for this project. Our group will also collaborate closely with Dr. Xiang Fang, the Medical Director of the Collaborative AD and Memory Disorders Program at UTMB; and with Dr. Inhan Lee, CEO of miRcore, and an expert in ncRNA bioinformatics; and with a senior biostatistician, Dr. Heidi Spratt, who will oversee statistics analysis and patient sample size determinations. This multidisciplinary research collaboration will help us to achieve our long-term goal of identifying biologically functional molecules that contribute to the onset and progression of AD. We expect this work will also contribute to development of methods for early diagnosis, prevention, monitoring, and potential therapeutic targets for AD.

项目概要/摘要 阿尔茨海默病（AD）是最常见的神经退行性疾病，临床测试的特异性较低 (<70%)，由于其病理生理过程在很大程度上尚不清楚。 由于非编码 RNA (ncRNA) 作为主要产品的发现，取得了显着进展 尽管最近的研究表明 ncRNA，尤其是 microRNA (miRNA) 和长链 ncRNA (lncRNA) 与 AD 的发展有关，只有有限数量的 miRNA/lncRNA- 发现了失调的途径，其中一些与发病、进展和发病的相关性值得怀疑。 此外，已知在 AD 中发生改变的 miRNA/lncRNA 并不总是 AD 特异性的，因为 这种变化也发生在其他神经退行性疾病中。此外，许多 ncRNA 的功能也发生变化。 AD，尤其是新兴的 ncRNA，我们最近的实验数据表明，AD 是未知的。 tRNA 衍生的 RNA 片段 (tRF)（最近发现的 ncRNA 家族）的表达谱 tRF 的一些变化比 miRNA 的变化更显着，并且 这些变化在 AD 患者中具有年龄和/或阶段依赖性的模式，在这里，我们勇敢地承认这一点。 tRF 是 AD 进展和发病机制的关键因素，我们将确定相关的 tRF 特征。 我们还将确定 AD 中异常 tRF 的目标（目标 2）。 我们在病毒感染和环境中发现 tRF 诱导和功能方面的研究经验 重金属污染物为我们提供了该项目所需的专业知识和工具。 与AD和记忆障碍协作中心医学主任方翔博士密切合作 UTMB 项目；与 miRcore 首席执行官、ncRNA 生物信息学专家 Inhan Lee 博士合作； 高级生物统计学家 Heidi Spratt 博士将负责监督统计分析和患者样本量 这种多学科研究合作将帮助我们实现我们的长期目标。 我们期望能够识别出有助于 AD 发生和进展的生物功能分子。 工作还将有助于开发早期诊断、预防、监测和潜在的方法 AD 的治疗目标。