权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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