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 转座元素（TES）约占人类DNA的25％，代表最大类 哺乳动物基因组中的生化功能性DNA元素。人类基因组中约8％的TE 是人内源性逆转录病毒（HERVS）。 HERV由一组促进 逆转录位和两个含有启动子的相同的长末端重复序列（LTR）；一个 完成HERV通常跨越几千套。大多数草药是碎片或孤独的LTR。自从他们 识别众多研究已在疾病过程中寻求HERV的病因作用 这表明在某些癌症，自身免疫性疾病和神经系统疾病中起因作用，这是 认为HERV的失调在神经变性和衰老的病理生理学中起着至关重要的作用。 在初步数据中，我们使用生物信息学管道望远镜来识别差异调节的HERV 在批量RNASEQ数据中，发现了跨大脑区域和神经元细胞的HERV表达的区域模式 广告和衰老类型。在Tauopathy小鼠模型中，我们还发现过度活跃的GMP-AMP 合成酶（CGA） - 干扰素基因（STING）信号传导（CGA）途径的刺激剂有助于TAU毒性 由于遗传降低了CGA受到防止TAU介导的空间学习和记忆缺陷的遗传减少 AD的Tauopathy小鼠模型。这使我们提出了这样的假设，即HERV是病毒核酸的来源 刺激导致神经炎症的CGA刺激，导致AD的病因。在三个特定目标中， 我们将首先表征和验证来自整个生命周期中细胞和脑样本的HERV表达， 从年龄和性别匹配AD的患者。使用我们的新生物信息学管道，stellarscope，我们将 确定具有基因座特异性精度的单核RNA测序数据的HERV差异表达。 其次，我们将确定由衰老和衰老调节的神经元相关基因和HERV表达途径 AD，使用直接诱导神经元的参与者衍生的细胞模型（INS）。与未成熟的神经元不同 由诱导多能干细胞产生的种群，INS保留神经元特异性，与衰老相关的基因 供体的表达特征。我们将确定HERV表达的差异是否反映了 加速的年龄和/或其他广告相关的转录特征可以通过 来自年龄匹配的年轻同龄人和年龄匹配的老年同龄人的INS的转录转录表型。 最后，我们将确定TE如何在AD的小鼠模型中引起tauopathy。我们将确定任何 CGA抑制剂对Tauopathy认知缺陷发作之前或之后的TE表达的有益作用 小鼠以及CGA删除是否会改变TE表达。我们将评估TES的抑制是否会保护 反对tauopathy，以及CGA的抑制剂如何改变TE表达。拟议研究的完成将 确定TE表达在衰老和AD中的新型机制，并为 药理干预。