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:
- 金额:$ 135.82万
- 依托单位:
- 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:
- 关键词:AgeAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease related dementiaAntiviral ResponseAutoimmune DiseasesBiochemicalBrainBrain regionCell AgingCell LineCell NucleusCell modelCellsCharacteristicsCognitive deficitsCyclic GMPDNADNA Transposable ElementsDataDiagnosticDiseaseElderlyElementsEndogenous RetrovirusesEnvironmental Risk FactorEtiologyExhibitsFibroblastsFunctional disorderGene ExpressionGene Expression ProfileGenesGeneticGenomicsGrantHumanHuman GenomeHyperactivityInterferon ActivationInterferon Type IInterventionLearningLigandsLong Terminal RepeatsLongevityMalignant NeoplasmsMediatingMemory impairmentModelingMusNatural ImmunityNerve DegenerationNeurodegenerative DisordersNeuronsNucleic AcidsParticipantPathway interactionsPatientsPatternPeripheral Blood Mononuclear CellPharmacologyPhenotypePhysiologicalPlayPopulationProcessRNARetrotranspositionRoleSamplingSex FactorsSignal TransductionSignaling ProteinSourceSpecificityStimulator of Interferon GenesStructureTauopathiesTherapeuticTissuesToxic effectValidationViralbasebioinformatics pipelinecell typecohortcytokinedifferential expressiongenotypic sexhealthy aginghuman DNAin silicoinduced pluripotent stem cellinhibitorinsightmammalian genomemouse modelnerve stem cellnervous system disorderneuroinflammationnovelnovel therapeuticspreservationpromoterrepositorysensorsextau Proteinstooltranscriptome 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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
DOUGLAS F NIXON其他文献
DOUGLAS F NIXON的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('DOUGLAS F NIXON', 18)}}的其他基金
Development of Brain Organoids to Study the Impact of HIV-1, Drugs of Abuse and Aging on Cognitive Impairment
开发大脑类器官来研究 HIV-1、滥用药物和衰老对认知障碍的影响
- 批准号:
10208846 - 财政年份:2020
- 资助金额:
$ 135.82万 - 项目类别:
Development of Brain Organoids to Study the Impact of HIV-1, Drugs of Abuse and Aging on Cognitive Impairment
开发大脑类器官来研究 HIV-1、滥用药物和衰老对认知障碍的影响
- 批准号:
10398244 - 财政年份:2020
- 资助金额:
$ 135.82万 - 项目类别:
Development of Brain Organoids to Study the Impact of HIV-1, Drugs of Abuse and Aging on Cognitive Impairment
开发大脑类器官来研究 HIV-1、滥用药物和衰老对认知障碍的影响
- 批准号:
10063343 - 财政年份:2020
- 资助金额:
$ 135.82万 - 项目类别:
Genetic Risk of HIV Acquisition: Mechanisms of Resilience
感染艾滋病毒的遗传风险:恢复机制
- 批准号:
10077116 - 财政年份:2020
- 资助金额:
$ 135.82万 - 项目类别:
Development of Brain Organoids to Study the Impact of HIV-1, Drugs of Abuse and Aging on Cognitive Impairment
开发大脑类器官来研究 HIV-1、滥用药物和衰老对认知障碍的影响
- 批准号:
10613440 - 财政年份:2020
- 资助金额:
$ 135.82万 - 项目类别:
Genetic Risk of HIV Acquisition: Mechanisms of Resilience
感染艾滋病毒的遗传风险:恢复机制
- 批准号:
10251347 - 财政年份:2020
- 资助金额:
$ 135.82万 - 项目类别:
Elimination of HIV using HERV specific T cells
使用 HERV 特异性 T 细胞消除 HIV
- 批准号:
9744988 - 财政年份:2019
- 资助金额:
$ 135.82万 - 项目类别:
HIV induced anti-cancer HERV immunity in prostate, breast and colon cancers
HIV 诱导前列腺癌、乳腺癌和结肠癌中的抗癌 HERV 免疫
- 批准号:
9129387 - 财政年份:2016
- 资助金额:
$ 135.82万 - 项目类别:
BELIEVE: Bench to Bed Enhanced Lymphocyte Infusions to Engineer Viral Eradication
相信:从床到床增强淋巴细胞输注可实现病毒根除
- 批准号:
9315726 - 财政年份:2016
- 资助金额:
$ 135.82万 - 项目类别:
相似海外基金
Interplay between Aging and Tubulin Posttranslational Modifications
衰老与微管蛋白翻译后修饰之间的相互作用
- 批准号:
24K18114 - 财政年份:2024
- 资助金额:
$ 135.82万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
EMNANDI: Advanced Characterisation and Aging of Compostable Bioplastics for Automotive Applications
EMNANDI:汽车应用可堆肥生物塑料的高级表征和老化
- 批准号:
10089306 - 财政年份:2024
- 资助金额:
$ 135.82万 - 项目类别:
Collaborative R&D
The Canadian Brain Health and Cognitive Impairment in Aging Knowledge Mobilization Hub: Sharing Stories of Research
加拿大大脑健康和老龄化认知障碍知识动员中心:分享研究故事
- 批准号:
498288 - 财政年份:2024
- 资助金额:
$ 135.82万 - 项目类别:
Operating Grants
Baycrest Academy for Research and Education Summer Program in Aging (SPA): Strengthening research competencies, cultivating empathy, building interprofessional networks and skills, and fostering innovation among the next generation of healthcare workers t
Baycrest Academy for Research and Education Summer Program in Aging (SPA):加强研究能力,培养同理心,建立跨专业网络和技能,并促进下一代医疗保健工作者的创新
- 批准号:
498310 - 财政年份:2024
- 资助金额:
$ 135.82万 - 项目类别:
Operating Grants
関節リウマチ患者のSuccessful Agingに向けたフレイル予防対策の構築
类风湿性关节炎患者成功老龄化的衰弱预防措施的建立
- 批准号:
23K20339 - 财政年份:2024
- 资助金额:
$ 135.82万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Life course pathways in healthy aging and wellbeing
健康老龄化和福祉的生命历程路径
- 批准号:
2740736 - 财政年份:2024
- 资助金额:
$ 135.82万 - 项目类别:
Studentship
NSF PRFB FY 2023: Connecting physiological and cellular aging to individual quality in a long-lived free-living mammal.
NSF PRFB 2023 财年:将生理和细胞衰老与长寿自由生活哺乳动物的个体质量联系起来。
- 批准号:
2305890 - 财政年份:2024
- 资助金额:
$ 135.82万 - 项目类别:
Fellowship Award
I-Corps: Aging in Place with Artificial Intelligence-Powered Augmented Reality
I-Corps:利用人工智能驱动的增强现实实现原地老龄化
- 批准号:
2406592 - 财政年份:2024
- 资助金额:
$ 135.82万 - 项目类别:
Standard Grant
McGill-MOBILHUB: Mobilization Hub for Knowledge, Education, and Artificial Intelligence/Deep Learning on Brain Health and Cognitive Impairment in Aging.
McGill-MOBILHUB:脑健康和衰老认知障碍的知识、教育和人工智能/深度学习动员中心。
- 批准号:
498278 - 财政年份:2024
- 资助金额:
$ 135.82万 - 项目类别:
Operating Grants
Welfare Enhancing Fiscal and Monetary Policies for Aging Societies
促进老龄化社会福利的财政和货币政策
- 批准号:
24K04938 - 财政年份:2024
- 资助金额:
$ 135.82万 - 项目类别:
Grant-in-Aid for Scientific Research (C)