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：
10302457
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/10302457
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 Immunoblotting 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 Repetitive Sequence Reporting Research Reverse Transcriptase Polymerase Chain Reaction Role Sampling Signal Transduction Structure System Testing Therapeutic Tissues Transcript Untranslated RNA 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.

衰老会增加患阿尔茨海默病（AD）的风险，但其潜在机制尚不明确下一代测序研究（例如转录组学、RNA-seq）有望用于鉴定。大脑衰老/AD 的新介质，但许多人只关注编码基因。 PAS-19-392，强调“阐明遗传和表观遗传因素、基因组稳定性、损伤、 AD 中的“和 DNA 修复”，在这个 R03 项目中，我们将探索基因组生物学中的一个新兴主题，该主题可能深入了解大脑衰老/AD 的新机制。具体来说，我们将确定是否与年龄相关。非编码重复元件（RE）转录物的积累是大脑衰老和衰老之间的重要联系 AD，我们将测试相关的治疗策略，我们的理由是 RE 转录本倾向于形成。可能会刺激神经炎症（一种主要且潜在的可靶向性）的双链 RNA (dsRNA) AD 机制）。 RE 转录本源自占人类基因组 60% 以上的非编码重复序列。它们在转录组研究中经常被忽视为“不活跃”，然而，越来越多的证据表明这一点。 RE 失调/激活直接导致衰老，某些药物干预可能会导致衰老一些证据还表明，选择性 RE 转录本在 AD 中有所增加，但我们的研究表明，初步数据表明：a) 全局 RE 转录水平（即不仅仅是选择 RE）随着时间的推移逐渐增加 b) 类似的 RE； AD 患者大脑和神经元中的转录物和 dsRNA 增加，并且 c) RE 转录物抑制可能；这些观察结果表明，与年龄相关的整体失调。 RE 转录本可能在大脑衰老和与年龄相关的 AD 中发挥核心作用，可能是通过引起 dsRNA 驱动我们将通过以下方式研究这种可能性：1）进行大规模生物信息学分析。多个 RNA-seq 数据集来识别与大脑相关的关键 RE 转录本和 RE 衍生的 dsRNA 衰老/AD 和神经炎症；2) 使用来自人类捐赠者的神经元来测试功效临床可转化的植物化学化合物可减少 RE/dsRNA 积累，从而抑制年龄/AD- 相关的神经炎症，并鉴定可能导致神经炎症和 AD 的 RE 衍生 dsRNA 通过刺激细胞 dsRNA 传感器蛋白激酶 R（PKR，与 AD 病理学相关）。这些研究将为未来的 R01 提供一个框架，研究年龄- 相关的 RE 转录本增加会导致大脑衰老/AD，并且 RE 靶向疗法有可能体内治疗或预防脑老化/AD。