Constructing A Transcriptomic Atlas of Retrotransposon in Alzheimer's Disease

构建阿尔茨海默病逆转录转座子转录组图谱

基本信息

批准号：
10431366
负责人：
Zhongming Zhao
金额：
$ 31.2万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10431366
关键词：
Aducanumab Aging Algorithms Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease patient Antiviral Agents Archives Atlases Autopsy Benchmarking Brain Brain region Cell Nucleus Cells Characteristics Chromatin Clinical Clinical Trials Communities Computing Methodologies DNA DNA Methylation DNA Sequence Data Data Set Databases Disease Drosophila genus Economic Burden Elements Endogenous Retroviruses Epigenetic Process Gene Expression Gene Proteins Genetic Diseases Genetic Transcription Genome Genomics Healthcare Human Human Genome Innate Immune Response Investigation Knowledge Mediating Medical center Memory Methods Methylation MicroRNAs Mining Molecular Multiomic Data Nerve Degeneration Neurodegenerative Disorders Nuclear Other Genetics Outcome Pathogenesis Pathogenicity Pathologic Processes Patients Pharmacotherapy Play Prevention Proteins Public Health Publishing RNA-Directed DNA Polymerase Regulation Relaxation Repression Research Research Personnel Resolution Resources Retrotransposon Reverse Transcription Role Signal Pathway Small Nuclear RNA Specificity Time Tissue Sample Tissues Transcript United States Update Visualization base brain tissue cell type complex data data resource design drug efficacy efficacy evaluation epigenetic silencing epigenome epigenomics expectation experience graph neural network histone modification human disease improved inhibitor innovation interest machine learning method novel religious order study sex statistical and machine learning tau Proteins tau aggregation tool trait transcriptome transcriptome sequencing transcriptomics transposon/insertion element treatment research user-friendly web portal web site

项目摘要

Project Summary The number of AD patients is gradually increasing every year, and the economic burden of health care of AD patients, estimated at $335 billion in 2021, is predicted to triple by 2050. In the interest of public health and the economy, understanding AD genetics and finding effective AD prevention and treatment are important. Numerous studies have suggested that AD is a complicated genetic disorder, often involving genomic structural changes and regulation. Thus, there is a strong need to investigate not only regular genes, proteins, and their regulations but also the other genetic components in AD. Retrotransposons (RTEs) are DNA sequences that copy themselves and insert their copies into the genome. There has been some interest in studying retrotransposons in AD research. For example, it is known that chromatin relaxation mediated by Tau protein accumulation may overly activate the retrotransposons. This massive activation may provoke an innate immune response and damage the genome, which can result in neurodegeneration. Moreover, a study showed that antiviral drugs could suppress activation of RTEs in AD by inhibiting their reverse transcriptase, and the suppression results in the prevention of neurodegeneration. These studies suggested that investigating the features and roles of retrotransposons in AD will provide an additional and important way to understand the regulations of RTEs in AD pathogenesis. However, molecular characteristics of the RTEs in AD, such as cell type-/sex-specificity, are still unknown. Characterizing RTEs requires generating large-scale RTE expression datasets. Such data has not been available publicly, although the AD research community has made tremendous efforts to generate large-scale postmortem AD transcriptome data, including bulk RNA-seq of ~2,000 subjects and single-cell nuclei RNA-seq of ~260,000 cells. Therefore, we propose two specific aims to perform the first systematic study of RTE by constructing an RTE atlas resource for AD study: Aim 1. To generate large-scale RTE expression datasets by mining and processing public AD transcriptome datasets. We will extend our SalmonTE algorithm to mine RTE expressions from AD transcriptome datasets at both tissue-level and single- cell resolution. Aim 2. To generate AD RTE atlas resources by characterizing RTEs and AD patients using statistical and machine learning methods. We will expand our in-house computational methods to calculate context-specificity (e.g., brain region, cell type, and sex) of each RTE in human AD brains. We will also develop an unsupervised graph neural network using RTE expression and multi-omics data to characterize AD patients. In the end, we will create an atlas website to share our findings with the AD research community. Successful completion of this project will provide 1) novel computational methods to rigorously characterize RTEs in AD, 2) identification of context-specific RTEs in AD and characterization of AD patients using RTE expression, and 3) a well-annotated AD RTE atlas to deepen our knowledge in the molecular basis of AD.

项目摘要AD患者的数量每年逐渐增加，经济负担 AD患者的卫生保健估计为2021年的3350亿美元，预计到2050年为三倍。健康与经济，了解AD遗传学以及发现有效的AD预防和治疗是重要的。大量研究表明AD是一种复杂的遗传疾病，通常涉及基因组结构变化和调节。因此，不仅需要研究常规基因，蛋白质，及其法规，以及AD中的其他遗传成分。逆转录座（RTE）是DNA 序列复制并将其副本插入基因组中。对研究AD研究中的逆转录子。例如，众所周知，由tau介导的染色质松弛蛋白质的积累可能会过度激活逆转录子。这种巨大的激活可能会引起先天性免疫反应和损害基因组，这可能导致神经退行性。此外，一项研究表明该抗病毒药物可以通过抑制其逆转录酶和抑制导致预防神经退行性。这些研究表明，调查逆转录座子在广告中的功能和角色将提供一种理解的其他重要方法 AD发病机理中RTE的法规。但是，AD中RTE的分子特性，例如细胞类型/性别特异性仍然未知。表征RTE需要生成大规模的RTE表达式数据集。尽管广告研究界已经巨大生成大规模验尸广告转录组数据的努力，包括约2,000名受试者的散装RNA-Seq 和约260,000个细胞的单细胞核RNA-Seq。因此，我们提出了两个具体目标，以执行第一个通过构建RTE地图集资源进行广告研究，对RTE进行系统研究：目标1。 RTE表达数据集通过挖掘和处理公共广告转录组数据集。我们将扩展我们的 Salmonte算法从组织级别和单一的AD转录组数据集中挖掘RTE表达式细胞分辨率。目标2。通过使用RTE和AD患者来表征AD RTE ATLAS资源统计和机器学习方法。我们将扩展内部计算方法以计算人类广告大脑中每个RTE的上下文特异性（例如，大脑区域，细胞类型和性别）。我们还将发展使用RTE表达和多摩学数据来表征AD患者的无监督图神经网络。最后，我们将创建一个地图集网站，以与广告研究社区分享我们的发现。成功的该项目的完成将提供1）严格表征AD中RTE的新型计算方法，2）使用RTE表达的AD和AD患者表征的上下文特异性RT鉴定，3）一个井井有条的AD ATLA，以AD的分子基础加深了我们的知识。