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.

项目总结/摘要 阿尔茨海默病（Alzheimer's disease，AD）是最常见的神经退行性疾病，临床检测特异性低 （<70%），由于其病理生理过程在很大程度上是未知的。基因组理解一直是 由于发现了非编码RNA（ncRNA）作为主要产物， 转录的基因组虽然最近的研究表明，ncRNA，特别是microRNA（miRNAs）和长 ncRNA（lncRNA）参与AD的发展，只有有限数量的miRNA/lncRNA- 确定了失调的途径，其中一些与疾病的发生、进展和 AD的发病机制此外，已知在AD中改变的miRNA/lncRNA并不总是AD特异性的， 这种变化也发生在其他神经退行性疾病中。此外，许多ncRNA在 AD，特别是新出现的ncRNA，尚不清楚。我们最近的实验数据表明， tRNA衍生的RNA片段（tRFs）的表达谱，最近确定的ncRNA家族， 在AD中有很大的影响。tRFs的一些变化比miRNAs的变化更显著， 这些变化在AD患者中具有年龄和/或阶段依赖性。在这里，我们假设， tRF是AD进展和发病机制的关键因素。我们将确定tRF特征 与AD严重程度和早发性AD（目的1）。我们还将确定AD中异常tRF的靶点（目的2）。 我们在发现tRF的诱导和功能在病毒感染和环境中的研究经验， 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。我们的团队也将 与合作性AD和记忆障碍的医学主任Xiang Fang博士密切合作 项目;与miRcore首席执行官Inhan Lee博士和ncRNA生物信息学专家;以及与 高级生物统计学家Heidi Spratt博士将监督统计分析和患者样本量 决心。这种多学科的研究合作将有助于我们实现我们的长期目标， 鉴定有助于AD发病和进展的生物学功能分子。我们预计这一 这项工作还将有助于发展早期诊断、预防、监测和潜在的 AD的治疗靶点。