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 该项目的目标是更好地了解RNA的调控和功能， 逆转录转座因子（RTEs）在阿尔茨海默病（AD），重点是 双链RNA（dsRNA）。RTE占据了人类基因组的大约40%。他们 构成转座子的一个主要亚组，定义为使用 涉及RNA中间体的“复制粘贴”机制。迄今为止，大多数RTE 失去了调动到新地点的能力，至少在正常的生理条件下。 然而，这些元件仍然可以通过表达RTE衍生的调节活性。 RNA。这种功能方面在人脑中特别相关，其中RTE表达 与其他组织相比是最高的。考虑到每个RTE家族的多拷贝性质， 转录物通常形成dsRNA结构，由重复序列内容、双向 转录或天然有义-反义转录物对。大量研究表明 细胞dsRNA的异常表达与各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存在增强的RNA表达 包括AD在内的神经退行性疾病的RTE。这种表达导致积累 在神经元中的dsRNA，这与，例如，细胞核TDP-43的损失或细胞核内的细胞 tau缠结。作为dsRNA积累的结果，I型IFN应答可在神经元中引发， 这可能有助于AD的发病机制。在这个项目中，我们的目标是确定身份， 来源于RTEs的AD相关dsRNA的起源，并通过实验验证其功能 神经元的相关性此外，我们还将研究RNA结合蛋白（包括 ADAR 1）对RTE衍生的dsRNA的作用及其与AD的功能相关性。这项工作将允许一个 以前未达到的水平的了解规则和功能的RTE衍生 dsRNA在AD中的作用，并为更好地了解RTE相关的疾病机制提供了新的见解。