Regulation and function of dsRNAs derived from retrotransposable elements in AD

AD 中逆转录转座元件衍生的 dsRNA 的调控和功能

• 批准号: 10518895
• 负责人: Xinshu Grace Xiao
• 金额: $ 63.69万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10518895
• 关键词: ADAR1; Address; Adenosine; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Autopsy; Brain; Cell Culture Techniques; Cell Differentiation process; Cells; Data; Development; Disease; Double-Stranded RNA; Elements; Enzymes; Family; Future; Gene Expression; Genes; Genetic Transcription; Genomics; Goals; Human; Human Genome; Inosine; Interferon Type I; Interferons; Lead; Link; Location; Mediating; Modeling; Natural Immunity; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Nuclear; Paste substance; Pathogenesis; Phenotype; Physiological; Production; Protein Isoforms; Proteins; Publishing; RNA; RNA Editing; RNA-Binding Proteins; Regulation; Repetitive Sequence; Research; Role; Sampling; Structure; Subgroup; Testing; Tissues; Transcript; Up-Regulation; Work; base; crosslinking and immunoprecipitation sequencing; ds RNA-Binding Proteins; experimental study; human disease; immunogenicity; inflammatory marker; insight; mind control; neurofibrillary tangle formation; novel diagnostics; novel therapeutic intervention; protein TDP-43; response; sensor; tau Proteins; transcriptome sequencing

Project Summary The goal of this project is to better understand the regulation and function of RNA derived from retrotransposable elements (RTEs) in Alzheimer’s disease (AD), with a focus on double-stranded RNAs (dsRNAs). RTEs occupy roughly 40% of the human genome. They constitute a major subgroup of transposons, defined as genomic sequences that mobilize using a ‘copy-and-paste’ mechanism where an RNA intermediate is involved. To date, most RTEs have lost the ability to mobilize to new locations, at least in normal physiological conditions. However, these elements may still retain regulatory activities through expression of RTE-derived RNAs. This functional aspect is particularly relevant in the human brain, where RTE expression is highest compared to other tissues. Given the multi-copy nature of each family of RTEs, their transcripts often form dsRNA structures, resulted from repetitive sequence content, bi-directional transcription or natural sense-antisense transcript pairs. Numerous studies have shown that aberrant expression of cellular dsRNAs is related to the pathogenesis of various human diseases. Recently, increasing evidence supports the existence of enhanced RNA expression from RTEs in neurodegenerative diseases, including AD. This expression leads to accumulation of dsRNAs in neurons, which is correlated with, for example, loss of nuclear TDP-43 or burden of tau tangles. As a result of dsRNA accumulation, type I IFN response may be elicited in neurons, which may contribute to AD pathogenesis. In this project, we aim to determine the identity and origin of AD-relevant dsRNAs derived from RTEs and experimentally validate their functional relevance in neurons. In addition, we will examine the impact of RNA-binding proteins (including ADAR1) on RTE-derived dsRNAs and their functional relevance to AD. This work will allow a previously unattained level of understanding of the regulation and function of RTE-derived dsRNAs in AD and provide new insights to better understand RTE-related disease mechanisms.

项目概要 该项目的目标是更好地了解源自RNA的调控和功能 阿尔茨海默病 (AD) 中的逆转录转座元件 (RTE)，重点是 双链 RNA (dsRNA) 约占人类基因组的 40%。 构成转座子的一个主要亚群，定义为利用基因组序列动员 迄今为止，大多数 RTE 都涉及 RNA 中间体的“复制粘贴”机制。 失去了移动到新地点的能力，至少在正常的生理条件下是这样。 然而，这些元件可能仍然通过 RTE 衍生的表达保留调节活性。 RNA 的这一功能与人脑尤其相关，其中 RTE 表达在人脑中。 与其他组织相比，考虑到每个 RTE 家族的多拷贝性质，它们的 转录物通常形成 dsRNA 结构，由重复序列内容产生，双向 大量研究表明，转录或自然有义-反义转录对。 细胞dsRNA的异常表达与多种人类的发病机制有关 最近，越来越多的证据支持 RNA 表达增强的存在。 来自神经退行性疾病（包括 AD）中的 RTE，这种表达会导致积累。 神经元中 dsRNA 的数量，这与核 TDP-43 的丢失或 tau 缠结是 dsRNA 积累的结果，可能会在神经元中引发 I 型 IFN 反应， 在这个项目中，我们的目标是确定可能导致 AD 发病机制的因素。 源自 RTE 的 AD 相关 dsRNA 的起源并通过实验验证其功能 此外，我们还将研究 RNA 结合蛋白（包括 RNA 结合蛋白）的影响。 ADAR1）研究 RTE 衍生的 dsRNA 及其与 AD 的功能相关性。 对 RTE 衍生的调节和功能的理解达到了前所未有的水平 dsRNA 在 AD 中的作用，并为更好地理解 RTE 相关疾病机制提供新的见解。