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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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

项目摘要

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/总结转座元件 (TE) 约占人类 DNA 的 25%，代表最大的一类哺乳动物基因组中具有生化功能的 DNA 元件。人类基因组中约 8% 的 TE 是人类内源性逆转录病毒（HERV）。 HERV 由一组基因（Gag、Pol、Env）组成，这些基因促进逆转录转座，以及位于这些基因侧翼的两个包含相同长末端重复序列 (LTR) 的启动子；一个完整的 HERV 通常跨越数千个碱基。大多数 HERV 是片段或单独的 LTR。自从他们的许多研究都在寻找 HERV 在疾病过程中的致病作用，并得出结论这表明它在某些癌症、自身免疫性疾病和神经系统疾病中具有致病作用，并且认为 HERV 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，我们使用生物信息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 表达区域模式 AD 和衰老的类型。在 tau 蛋白病小鼠模型中，我们还发现过度活跃的环 GMP-AMP 合成酶 (cGAS) - 干扰素基因刺激剂 (STING) 信号传导 (cGAS) 途径导致 tau 毒性因为 cGAS 的遗传减少可以防止 tau 介导的空间学习和记忆缺陷 AD tau蛋白病小鼠模型。这使我们得出这样的假设：HERV 是病毒核酸的来源，刺激 cGAS-STING 导致神经炎症，导致 AD 的病因。在三个具体目标中，我们将首先表征并验证整个生命周期的细胞和大脑样本中的 HERV 表达，以及年龄和性别匹配的 AD 患者。使用我们新的生物信息学管道 Stellarscope，我们将以位点特异性精度从单核 RNA 测序数据确定 HERV 的差异表达。其次，我们将确定受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 (iN) 的参与者衍生细胞模型。与未成熟的神经元不同由诱导多能干细胞产生的群体，iNs 保留了神经元特异性、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/或额外的 AD 相关转录特征通过来自年龄匹配的年轻队列和年龄匹配的老年队列的 iN 的逆转录表型。最后，我们将确定 TE 如何在 AD 小鼠模型中引起 Tau 病。我们将确定任何 cGAS 抑制剂对 tau 蛋白病认知缺陷发作前后 TE 表达的有益影响小鼠以及 cGAS 缺失是否会改变 TE 表达。我们将评估抑制 TE 是否能够保护对抗 tau 蛋白病，以及 cGAS 抑制剂如何改变 TE 表达。完成拟议的研究将确定衰老和 AD 中 TE 表达的新机制，并为治疗提供新的方向药物干预。