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

项目摘要/摘要 阿尔茨海默病(AD)是最常见的神经退行性疾病，临床试验的特异性较低 (&lt；70%)，这是由于其病理生理过程在很大程度上是未知的。基因组的理解一直是 由于发现了作为主要产物的非编码RNA(NcRNAs)，显著进步了 转录的基因组。尽管最近的研究表明，ncRNAs，特别是microRNAs(MiRNAs)和Long NcRNAs(LncRNAs)，与AD的发展有关，只有有限数量的miRNAs/lncRNAs- 发现了失调的通路，其中一些与发病、进展和 阿尔茨海默病发病机制。此外，已知在AD中改变的miRNAs/lncRNAs并不总是AD特有的，因为 这种变化也发生在其他神经退行性疾病中。此外，许多ncRNAs在体内的功能 AD，特别是新兴的ncRNA，目前尚不清楚。我们最近的实验数据表明， TRNA衍生的RNA片段(TRFs)是最近发现的一个ncRNAs家族，其表达谱被 在AD中受到显著影响。TRFs的一些变化比miRNAs的变化更显著，并且 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 TRFs是AD进展和发病机制的关键因素。我们将确定相关的TRF签名 伴AD严重程度和早发性AD(目标1)。我们还将确定AD中异常TRFs的靶点(目标2)。 我们在发现TRF在病毒感染和环境中的诱导和功能方面的研究经验 重金属污染物为我们提供了这个项目所需的专业知识和工具。我们的团队也将 与协作性AD和记忆障碍医学主任项芳博士密切合作 UTMB计划；与miRcore首席执行官、ncRNA生物信息学专家Inhan Lee博士；以及与 高级生物统计师海蒂·斯普拉特博士将负责统计分析和患者样本量 决定。这种多学科的研究合作将帮助我们实现我们的长期目标 识别有助于AD发病和进展的生物功能分子。我们预料到了这一点 工作还将有助于开发早期诊断、预防、监测和潜力的方法。 AD的治疗靶点。

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.