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: 10333657
• 负责人: John M Sedivy
• 金额: $ 331.02万
• 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/10333657
• 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; Amyloid beta-42; Amyotrophic Lateral Sclerosis; Antiviral Response; Astrocytes; Autopsy; Behavioral; Benign; Biological Models; Biology; Cell Aging; Cell Line; Cells; Chromatin; Clinical; Clinical Trials; Complementary DNA; DNA Damage; Dementia; Detection; Disease; Drosophila genus; Elderly; Elements; Epigenetic Process; Event; Failure; Fibroblasts; Fright; Funding; Generations; Genetic; Genetic Screening; Genome; Genomics; Goals; Health; Host Defense; Host Defense Mechanism; Human; Human Genome; Image; Immune signaling; Induced pluripotent stem cell derived neurons; Inflammation; Innate Immune System; Interferon Type I; Interferons; Invaded; Investigation; L1 Elements; Lead; Length; Link; Location; Long Interspersed Elements; Long Terminal Repeats; Long-Term Effects; Longevity; Malignant Neoplasms; Messenger RNA; Methods; Microglia; Modeling; Molecular; Mus; Mutation; Natural Immunity; Nerve Degeneration; Neuraxis; 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; Ursidae Family; Validation; Virus; age related; aged; base; bioinformatics tool; derepression; design; falls; gene therapy; genomic tools; healthspan; immune activation; in vivo; induced pluripotent stem cell; inhibitor; inhibitor therapy; interest; member; molecular imaging; mouse model; nervous system disorder; neuroinflammation; neuropathology; neurotoxicity; novel; parasitism; programs; pseudotoxoplasmosis syndrome; response; single molecule; single-cell RNA sequencing; stem cell model; tau Proteins; 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） 逆转录转座因子（RTEs）占人类基因组的45%。被称为“移动的DNA”， 使用“复制和粘贴”机制插入新的基因组位置。这个过程，反转录，可以是 在多个层面上有害，并在很大程度上被视为分子寄生。毫不奇怪，宿主器官- ISMS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 RTEs和它们的宿主之间的关系在基因组序列的进化记录中是明显的。这 关于体细胞组织中RTEs活性的记录是沉默的，因为这种信息不是从一代传下来的 另一个，而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， 有证据表明，躯体RTE活动比预期的更频繁， 提供了重要的早期证据。五年前，这场辩论最终导致提交了这份《方案规划》， 建立在这样的假设上，即RTEs的体细胞激活代表了一种新的、迄今为止未被认识的 分子老化过程我们的研究计划旨在验证这一假设，并阐明基本的- 的机制。在接下来的五年里，这一假设得到了验证，不仅是我们的团队， 其他各组现在很明显，随着年龄的增长，多种宿主防御机制受到损害， 通常，重复序列，而不仅仅是活性RTE，增加它们的表达。关于隐藏的机械- 这种躯体攻击“会伤害我们”的说法让我们大吃一惊：我们发现RTE是-- 在衰老过程中受到挤压的元件，特别是LINE-1（L1）元件，可以产生位于细胞质中的cDNA逆转录酶。 成绩单这些cDNA是I型干扰素（IFN-I）反应的有效激活剂，其反过来刺激细胞内的细胞因子。 先天免疫系统我们认为这会导致一种被称为“无菌炎症”或“炎症”的现象- “成像”是一种已知的衰老标志，与多种年龄相关疾病有关。简而言之， 宿主生物体将RTE激活视为入侵病毒，并产生适当的抗病毒应答 - 不幸的是，鉴于入侵者嵌入在我们的基因组中，这种反应是徒劳的，最终无法... 多产的有趣的是，中枢神经系统（CNS）似乎是RTE活动的“特权部位”， 具有相对高的表达水平并且易于进一步上调。多条证据表明， RTE激活与病理学相关，特别是神经炎症。神经退行性疾病， 特别是痴呆症，如阿尔茨海默氏病（AD），是最具破坏性和最令人恐惧的疾病之一， 衰老的疾病。这个PPG的目标是详细探索新发现的L1体细胞生命周期， 中枢神经系统的神经元和非神经元细胞，中枢神经系统中的L1监视机制，它们如何失败， 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 死后组织F.H.盖奇，一个广为人知的广告先驱，加入了原来的PPG团队在这个追求。