Role of age-dependent repetitive element transcript dysregulation in Alzheimers disease

年龄依赖性重复元件转录失调在阿尔茨海默病中的作用

基本信息

批准号：
10468222
负责人：
Thomas LaRocca
金额：
$ 15.2万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468222
关键词：
Address Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Area Autophagocytosis Biochemical Bioinformatics Biological Biological Assay Biological Markers Biology Brain Chromatin Code Complement Cross-Sectional Studies DNA Repair Data Data Set Development Double-Stranded RNA Elderly Elements Endogenous Retroviruses Enzyme-Linked Immunosorbent Assay Epigenetic Process Event Fibroblasts Fluorescent in Situ Hybridization Funding Future Genes Genetic Genetic Transcription Genome Genome Stability Human Human Genome Impaired cognition Impairment Inflammaging Inflammation Innate Immune Response Intervention Junk DNA Lead Link Longitudinal Studies Maintenance Mediator of activation protein Modeling Neurodegenerative Disorders Neurons Pathology Peripheral Pharmacology Phenotype Phytochemical Play Positioning Attribute Publishing Quality Control RNA RNA metabolism RNA-targeting therapy Repetitive Sequence Reporting Research Reverse Transcriptase Polymerase Chain Reaction Role Sampling Signal Transduction System Testing Therapeutic Tissues Transcript Untranslated RNA Western Blotting Work age related aging brain anti aging base clinically translatable cognitive function cytokine efficacy testing follow-up human tissue in vivo insight neuroinflammation next generation sequencing novel novel strategies prevent protein kinase R response sensor targeted treatment tau Proteins therapeutic target transcriptome transcriptome sequencing transcriptomics

项目摘要

Aging increases the risk for Alzheimer’s disease (AD), but the underlying mechanisms are poorly understood. Next-generation sequencing studies (e.g., transcriptomics, RNA-seq) hold promise for identifying novel mediators of brain aging/AD, but many have focused on coding genes only. Therefore, in response to PAS-19-392, which emphasizes the “elucidation of genetic and epigenetic factors, genome stability, damage, and DNA repair” in AD, in this R03 project we will explore an emerging topic in genome biology that may provide insight into novel mechanisms of brain aging/AD. Specifically, we will determine if an age-related accumulation of non-coding repetitive element (RE) transcripts is an important link between brain aging and AD, and we will test related therapeutic strategies. Our rationale is that RE transcripts are predisposed to form double-stranded RNA (dsRNA) that may stimulate neuroinflammation (a major and potentially targetable mechanism of AD). RE transcripts are derived from non-coding repetitive sequences that make up >60% of the human genome. They are often ignored in transcriptome studies as “inactive”. However, growing evidence demonstrates that dysregulation/activation of RE contributes directly to aging, and that certain pharmacological interventions may prevent their effects. Some evidence also indicates that select RE transcripts are increased in AD, but our preliminary data show that: a) global RE transcript levels (i.e., not just select RE) increase progressively with age in human peripheral tissues, brains and neurons, and are associated with greater dsRNA; b) similar RE transcripts and dsRNA are increased in AD patient brains and neurons; and c) RE transcript suppression may inhibit neuro-inflammatory signaling. These observations suggest that an age-related, global dysregulation of RE transcripts could play a central role in brain aging and age-related AD, perhaps by causing dsRNA-driven neuroinflammation. We will investigate this possibility by: 1) conducting a large-scale bioinformatics analysis of multiple RNA-seq datasets to identify key RE transcripts and RE-derived dsRNAs associated with brain aging/AD and neuroinflammation; and 2) using neurons derived from human donors to test the efficacy of clinically translatable, phytochemical compounds that reduce RE/dsRNA accumulation for inhibiting age/AD- related neuroinflammation, and to identify the RE-derived dsRNAs that may cause neuroinflammation and AD by stimulating the cellular dsRNA sensor protein kinase R (PKR, which has been linked with AD pathology). These studies will provide a framework for a future R01 investigating the specific mechanisms by which age- related RE transcript increases contribute to brain aging/AD and the potential for RE-targeting therapies to treat or prevent brain aging/AD in vivo.

衰老增加了阿尔茨海默氏病（AD）的风险，但潜在的机制很差理解齿。下一代测序研究（例如，转录组学，RNA-seq）有望识别大脑衰老/AD的新型介体，但许多人仅专注于编码基因。因此，回应 PAS-19-392强调“阐明遗传和表观遗传因素，基因组稳定性，损伤，在AD中，在这个R03项目中，我们将探索一个基因组生物学的新兴话题提供有关大脑衰老/AD的新型机制的洞察力。具体来说，我们将确定是否与年龄有关非编码重复元件（RE）成绩单的积累是大脑衰老与广告，我们将测试相关的治疗策略。我们的理由是，重新成绩单倾向于形成双链RNA（dsRNA）可能刺激神经炎症（主要且潜在的目标 AD机制）。 RE转录本是从占人类基因组> 60％的非编码重复序列得出的。在转录组研究中，它们通常被忽略为“无活动”。但是，越来越多的证据表明 RE的失调/激活直接导致衰老，某些药物干预措施可能防止其影响。一些证据还表明，AD中的某些重新成绩单有所增加，但是我们初步数据显示：a）全局重新成绩单级别（即，不仅选择re）随着人类周围组织，大脑和神经元的年龄，与更大的dsRNA有关。 b）类似的回复在AD患者的大脑和神经元中，转录本和DSRNA增加； c）抑制笔录可能抑制神经炎症信号传导。这些观察结果表明，与年龄相关的全球失调转录本可以在大脑衰老和与年龄相关的AD中发挥核心作用，也许是通过引起DSRNA驱动的神经炎症。我们将通过：1）进行大规模生物信息学分析来调查这种可能性多个RNA-seq数据集，以识别与大脑相关的密钥重新记录和重新衍生的DSRNA 衰老/AD和神经炎症； 2）使用源自人供体的神经元测试的效率临床上可翻译的植物化学化合物，可减少抑制年龄/ad-的RE/dsRNA积累相关的神经炎症，并确定可能导致神经炎症和AD的重新衍生的DSRNA 通过刺激细胞DSRNA传感器蛋白激酶R（PKR，已与AD病理学联系在一起）。这些研究将为未来的R01提供一个框架，该R01研究了年龄的特定机制相关的重新记录增加有助于大脑衰老/AD，并有可能重新定位疗法治疗或预防体内大脑衰老/AD。