The Role of Transposable Elements in Healthy Aging and in Alzheimer's Disease

转座元件在健康衰老和阿尔茨海默病中的作用

• 批准号: 10670482
• 负责人: DOUGLAS F NIXON
• 金额: $ 135.82万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10670482
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Antiviral Response; Autoimmune Diseases; Biochemical; Brain; Brain region; Cell Aging; Cell Line; Cell Nucleus; Cell model; Cells; Characteristics; Cognitive deficits; Cyclic GMP; DNA; DNA Transposable Elements; Data; Diagnostic; Disease; Elderly; Elements; Endogenous Retroviruses; Environmental Risk Factor; Etiology; Exhibits; Fibroblasts; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Genetic; Genomics; Grant; Human; Human Genome; Hyperactivity; Interferon Activation; Interferon Type I; Intervention; Learning; Ligands; Long Terminal Repeats; Longevity; Malignant Neoplasms; Mediating; Memory impairment; Modeling; Mus; Natural Immunity; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nucleic Acids; Participant; Pathway interactions; Patients; Pattern; Peripheral Blood Mononuclear Cell; Pharmacology; Phenotype; Physiological; Play; Population; Process; RNA; Retrotransposition; Role; Sampling; Sex Factors; Signal Transduction; Signaling Protein; Source; Specificity; Stimulator of Interferon Genes; Structure; Tauopathies; Therapeutic; Tissues; Toxic effect; Validation; Viral; base; bioinformatics pipeline; cell type; cohort; cytokine; differential expression; genotypic sex; healthy aging; human DNA; in silico; induced pluripotent stem cell; inhibitor; insight; mammalian genome; mouse model; nerve stem cell; nervous system disorder; neuroinflammation; novel; novel therapeutics; preservation; promoter; repository; sensor; sex; tau Proteins; tool; transcriptome sequencing

PROJECT ABSTRACT/SUMMARY Transposable Elements (TEs) comprise roughly 25% of human DNA and represent the largest class of biochemically functional DNA elements in mammalian genomes. Around 8% of the TEs in the human genome are human endogenous retroviruses (HERVs). A HERV consists of a set of genes (Gag, Pol, Env) that facilitate retrotransposition, and two promoter-containing identical long terminal repeats (LTRs) that flank these genes; a complete HERV typically spans several kilobases. Most HERVs are fragments or solitary LTRs. Since their identification numerous studies have looked for causative roles for HERVs in disease processes with findings that suggest a causative role in some cancers, autoimmune disorders and neurological disorders, and it is thought that dysregulation of HERVs plays a critical role in the pathophysiology of neurodegeneration and aging. In preliminary data, we have used our bioinformatic pipeline Telescope to identify differentially regulated HERVs in bulk RNAseq data and found district patterns of HERV expression across brain regions and neuronal cell types in AD and aging. In a tauopathy mouse model, we also found that the hyperactive Cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) signaling (cGAS) pathway contributes to tau toxicity since genetic reduction of cGAS protected against tau-mediated spatial learning and memory deficits in a tauopathy mouse model of AD. This led us to the hypothesis that HERVs are a source of viral nucleic acid that stimulate cGAS-STING leading to neuroinflammation, contributing to the etiology of AD. In three specific aims, we will first characterize and validate HERV expression from cell and brain samples from across the lifespan, and from age and sex matched patients with AD. Using our new bioinformatics pipeline, Stellarscope, we will determine differential expression of HERVs from single-nuclei RNA-sequencing data with loci-specific precision. Second, we will determine neuronal-associated gene- and HERV-expression pathways modulated by aging and AD, using participant-derived cell models of directly induced neurons (iNs). Unlike the immature neuronal populations generated from induced pluripotent stem cells, iNs retain neuron-specific, aging-associated gene- expression characteristics of the donor. We will determine if differences in HERV expression are reflective of accelerated age- and/or additional AD-associated transcriptional signatures are evident through the retrotranscriptional phenotyping of iNs derived from age-matched young cohorts and age-matched elder cohorts. Finally, we will ascertain how TEs can cause Tauopathy in a mouse model of AD. We will determine any beneficial effects of a cGAS inhibitor on TE expression before or after the onset of cognitive deficit in tauopathy mice and whether cGAS deletion changes TE expression. We will assess whether suppression of TEs will protect against tauopathy, and how inhibitors of cGAS change TE expression. Completion of the proposed study will identify novel mechanisms of TE expression in aging and in AD, and provide new therapeutic directions for pharmacological intervention.

项目摘要/摘要 转座元件(TES)约占人类DNA的25%，是最大的一类 哺乳动物基因组中具有生物化学功能的DNA元件。人类基因组中约8%的TES 人类内源性逆转录病毒(HERV)。HERV由一组基因(Gag、Pol、Env)组成，这些基因有助于 逆转录转座，以及位于这些基因两侧的两个含有相同启动子的长末端重复序列(LTRs)； 完整的Herv通常跨越几千个碱基。大多数HERV是碎片或孤立的LRT。因为他们的 许多研究都在寻找HERV在疾病过程中的致病作用 这表明它在一些癌症、自身免疫性疾病和神经疾病中起到了致病作用，而且它是 认为HERV的调节失调在神经退行性变和衰老的病理生理学中起着关键作用。 在初步数据中，我们已经使用我们的生物信息管道望远镜来识别不同调控的HERV 在大量的RNAseq数据中，发现了HERV在脑区和神经细胞中表达的区域模式 AD的类型和年龄。在一种直立性病变小鼠模型中，我们还发现，过度活跃的环状GMP-AMP 合成酶(CGAS)-干扰素基因刺激物(STING)信号通路(CGAS)与tau毒性有关 由于cGAs的基因减少保护了tau介导的空间学习和记忆缺陷 阿尔茨海默病小鼠模型的建立。这导致了我们的假设，即HERV是病毒核酸的来源 刺激cGAS-刺痛导致神经炎症，导致AD的病因。在三个具体目标中， 我们将首先从整个生命周期的细胞和大脑样本中鉴定和验证Herv的表达， 并从年龄和性别上匹配AD患者。使用我们新的生物信息学管道，StellarScope，我们将 根据单核RNA测序数据，以特定位点的精度确定HERV的差异表达。 第二，我们将确定神经元相关基因和HERV表达途径受衰老和 AD，使用参与者衍生的直接诱导神经元(INS)细胞模型。与未成熟的神经元不同 由诱导的多能干细胞产生的群体，INS保留了神经元特异的、衰老相关的基因- 供者的表达特征。我们将确定HERV表达的差异是否反映了 加速的年龄和/或额外的AD相关转录签名通过 来自年龄匹配的年轻队列和年龄匹配的老年队列的INS的逆转录表型。 最后，我们将确定TES如何在阿尔茨海默病小鼠模型中引起肌张力障碍。我们将确定任何 CGAS抑制剂对颈椎病认知障碍发病前后TE表达的有利影响 以及cGAS缺失是否会改变TE的表达。我们将评估抑制工商业污水附加费是否会保护 以及cGAS的抑制剂如何改变TE的表达。建议的研究完成后， 明确TE在衰老和AD中表达的新机制，为AD的治疗提供新的方向 药物干预。