Role of Retrotransposon Activity in Neurodegeneration and Alzheimer's Disease

逆转录转座子活性在神经退行性变和阿尔茨海默氏病中的作用

• 批准号: 10581509
• 负责人: John M Sedivy
• 金额: $ 323.99万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581509
• 关键词: ATAC-seq; Adult; Age; Age related macular degeneration; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyloid; Amyotrophic Lateral Sclerosis; Antiviral Response; Astrocytes; Autopsy; Behavioral; Benign; Biological Models; Biology; Cell Aging; Cells; Central Nervous System; Chromatin; Clinical; Clinical Trials; Complementary DNA; Cytoplasm; DNA Damage; Dementia; Detection; Disease; Drosophila genus; Elderly; Elements; Epigenetic Process; Event; Failure; Fibroblasts; Fright; Funding; Generations; Genetic; Genetic Screening; Genome; Goals; Health; Host Defense; Host Defense Mechanism; Human; Human Genome; Image; Immune signaling; Induced pluripotent stem cell derived neurons; Inflammaging; Inflammation; Innate Immune System; Interferon Type I; Interferons; Invaded; Investigation; Length; Life Cycle Stages; Link; Long Interspersed Elements; Long Terminal Repeats; Long-Term Effects; Longevity; Malignant Neoplasms; Messenger RNA; Methods; Microglia; Modeling; Molecular; Mus; Mutation; Natural Immunity; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nucleic Acids; Nucleosides; Organism; Parasites; Paste substance; Pathology; Pathway interactions; Patients; Pharmacotherapy; Phenotype; Process; Proteins; Quality Control; RNA-Directed DNA Polymerase; Regulation; Repetitive Sequence; Reporter; Research; Research Personnel; Research Project Grants; Retrotransposition; Retrotransposon; Retroviridae Infections; Reverse Transcriptase Inhibitors; Role; Short Interspersed Nucleotide Elements; Signal Pathway; Site; Somatic Cell; Standardization; Sterility; Stress; System; Testing; Therapeutic Intervention; Tissue Harvesting; Tissues; Transcript; Untranslated RNA; Up-Regulation; Validation; Virus; age related; aged; bioinformatics tool; derepression; design; falls; gene therapy; genomic locus; genomic tools; healthspan; immune activation; in vivo; induced pluripotent stem cell; inhibitor therapy; interest; member; molecular imaging; mouse model; nervous system disorder; neuroinflammation; neuropathology; neurotoxicity; novel; parasitism; postmitotic; programs; pseudotoxoplasmosis syndrome; response; single molecule; single-cell RNA sequencing; stem cell model; tau Proteins; technology platform; therapy development; tool; transposon/insertion element

PROJECT SUMMARY (OVERALL) Retrotransposable elements (RTEs) comprise ~45% of the human genome. Known as ‘mobile DNA’ they can insert into new genomic locations using a 'copy and paste' mechanism. This process, retrotransposition, can be deleterious at multiple levels, and has largely been viewed as molecular parasitism. Not surprisingly, host organ- isms have evolved multiple silencing mechanisms to protect their genomes. This competitive and adversarial relationship between RTEs and their hosts is evident in the evolutionary record of genome sequences. This record is silent on the activity of RTEs in somatic tissues, since this information is not passed from one generation to another, and RTEs were thought to be largely silent in somatic cells. However, in the past 10-15 years evi- dence started emerging that somatic RTE activity is more frequent than anticipated, with members of this PPG contributing important early evidence. Five years ago, this debate culminated in the submission of this PPG, founded on the hypothesis that the somatic activation of RTEs represents a novel and hitherto unappreciated molecular aging process. Our research program was designed to test this hypothesis and elucidate the underly- ing mechanisms. The next five years saw a validation of this hypothesis, not just by our team, but also many other groups. It is now apparent that with aging, multiple host defense mechanisms become compromised, and repetitive sequences in general, not just active RTEs, increase their expression. As to the underlying mecha- nisms by which this somatic onslaught 'can hurt us' we were in for a surprise: we discovered that RTEs dere- pressed during aging, in particular LINE-1 (L1) elements, can generate cytoplasmically localized cDNA reverse transcripts. These cDNAs are potent activators of a Type-I Interferon (IFN-I) response, which in turn stimulates the innate immune system. We believe this leads to a phenomenon known as 'sterile inflammation' or 'inflam- maging', a known hallmark of aging that has been implicated in a variety of age-related diseases. In a nutshell, the host organism perceives RTE activation as an invading virus and mounts an appropriate anti-viral response – unfortunately, given that the invader is embedded in our genomes, this response is futile and ultimately coun- terproductive. Interestingly, the central nervous system (CNS) appears to be a 'privileged site' for RTE activity, with relatively high levels of expression and ease of further upregulation. Multiple lines of evidence indicate that RTE activation is associated with pathology, and in particular neuroinflammation. Neurodegenerative diseases, and in particular dementias such as Alzheimer's Disease (AD), are among the most devastating and feared diseases of aging. The goal of this PPG will be to explore in detail the newly discovered somatic L1 lifecycles in neuronal and non-neuronal cells of the CNS, the L1 surveillance mechanisms in the CNS, how they fail, the consequences of that failure, and ultimately, how we can fix this. We will use human induced pluripotent stem cell (iPSC) models as well as directly reprogrammed neurons, Drosophila and mouse models of AD, and human postmortem tissue. F.H. Gage, a widely-known AD pioneer, joins the original PPG team on this quest.

项目概要（总体） 逆转录转座元件 (RTE) 约占人类基因组的 45%，被称为“移动 DNA”。 使用“复制和粘贴”机制插入新的基因组位置，这个过程，逆转录转座，可以是。 在多个层面上都是有害的，并且在很大程度上被视为分子寄生，这并不奇怪。 主义已经进化出多种沉默机制来保护它们的基因组，这种竞争性和对抗性。 RTE 与其宿主之间的关系在基因组序列的进化记录中显而易见。 体组织中 RTE 的活动没有记录，因为该信息不是从一代人传递的 另一个观点是，RTEs被认为在体细胞中基本上是沉默的，然而，在过去的10-15年里，RTEs被认为在体细胞中基本上是沉默的。 该 PPG 成员开始发现体细胞 RTE 活动比预期更频繁 五年前，这场辩论最终导致了这份 PPG 的提交， 基于 RTE 的体细胞激活代表了一种新颖且迄今为止未被重视的假设 我们的研究计划旨在检验这一假设并阐明其根本原因。 接下来的五年里，这个假设得到了验证，不仅是我们的团队，还有许多团队。 现在很明显，随着年龄的增长，多种宿主防御机制会受到损害，并且 一般而言，重复序列（不仅仅是活跃的 RTE）会增加其表达。 这种身体攻击“会伤害我们”的主义让我们大吃一惊：我们发现RTEs dere- 衰老过程中受到挤压，特别是 LINE-1 (L1) 元件，可以产生细胞质定位的 cDNA 反向序列 这些 cDNA 是 I 型干扰素 (IFN-I) 反应的有效激活剂，进而刺激 I 型干扰素 (IFN-I) 反应。 我们相信这会导致一种称为“无菌炎症”或“炎症”的现象。 简而言之，“衰老”是一种已知的衰老标志，与多种与年龄相关的疾病有关。 宿主有机体将 RTE 激活视为入侵病毒，并采取适当的抗病毒反应 – 不幸的是，鉴于入侵者已嵌入我们的基因组中，这种反应是徒劳的，最终会导致 - 暗示，中枢神经系统（CNS）似乎是 RTE 活动的“特权部位”， 具有相对较高的表达水平并且易于进一步上调。 RTE 激活与病理学相关，特别是神经退行性疾病。 尤其是阿尔茨海默病 (AD) 等痴呆症，是最具破坏性和最令人恐惧的疾病之一 该 PPG 的目标是详细探索新发现的体细胞 L1 生命周期。 CNS 的神经元和非神经元细胞、CNS 中的 L1 监视机制、它们如何失效、 失败的后果，以及最终我们如何解决这个问题，我们将使用人类诱导多能干细胞。 细胞 (iPSC) 模型以及直接重编程的神经元、AD 的果蝇和小鼠模型以及人类 F.H. Gage 是一位广为人知的 AD 先驱，他加入了最初的 PPG 团队来完成这一任务。