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.

项目摘要 本项目的目标是更好地了解源于 阿尔茨海默病(AD)中的逆转座子(RTE)，重点是 双链RNA(DsRNA)。Rte约占人类基因组的40%。他们 构成转座子的一个主要亚群，定义为利用 一种‘复制-粘贴’机制，其中涉及RNA中间体。到目前为止，最多的RTE 已经失去了动员到新地点的能力，至少在正常的生理条件下是这样。 然而，这些元件仍然可能通过RTE衍生的表达而保留调节活性 RNA。这一功能方面在人脑中尤其相关，在那里RTE表达 与其他组织相比是最高的。鉴于每个RTE家族的多副本性质，他们的 转录本通常形成dsRNA结构，由重复的序列内容引起，双向的 转录或自然正义-反义转录物对。大量研究表明， 细胞dsRNAs的异常表达与多种人类疾病的发病机制有关 疾病。最近，越来越多的证据支持增强的RNA表达的存在 来自包括阿尔茨海默病在内的神经退行性疾病的RTE。这一表达导致了积累 在神经元中的dsRNAs的表达，这与例如核TDP-43的丢失或 牛排纠缠在一起。作为dsRNA积累的结果，I型干扰素反应可能在神经元中被激发， 这可能与AD的发病机制有关。在这个项目中，我们的目标是确定身份和 源于RTE的AD相关dsRNA的来源及其功能的实验验证 神经元的相关性。此外，我们还将研究RNA结合蛋白(包括 ADAR1)在RTE衍生的dsRNA上及其与AD的功能相关性。这项工作将允许 对RTE衍生的调节和功能的理解达到以前没有达到的水平 DsRNA在AD中的作用，为更好地理解RTE相关的疾病机制提供了新的见解。