The impact of LINE-1 retrotransposons on life span, SASP, and telomeres in vivo
LINE-1逆转录转座子对体内寿命、SASP和端粒的影响
基本信息
- 批准号:9764227
- 负责人:
- 金额:$ 33.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-15 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAffectAgeAnimal ModelAttenuatedBiologicalBiological AssayCancer PatientCell AgingCell physiologyCellsCentenarianCultured CellsCustomDNADNA DamageDNA Double Strand BreakDNA RepairDNA Repair PathwayDataDefectDeteriorationDevelopmentDiseaseDoseElementsFunctional disorderFutureGene FrequencyGeneticGenetic MarkersGenetic screening methodGenomeGenomic DNAGenomic InstabilityGenomicsGoalsHealthHeritabilityHumanHuman GenomeIn VitroIndividualIndolentInterleukin-6LeadLengthLocationLong Interspersed ElementsLongevityLungMalignant neoplasm of prostateMeasurableMessenger RNAMethodsModelingMutationNormal tissue morphologyOrganPhenotypePopulationRat TransgeneRattusReportingRetrotranspositionRetrotransposonRiskRisk FactorsSamplingSomatic CellSourceSpecificitySystemTelomeraseTelomere ShorteningTestingTestisTimeTissuesTransgenesTransgenic OrganismsVariantcohortendonucleasegenetic elementgenome wide association studyhuman tissuein vivomRNA Expressionmammalian genomemiddle agemutantnoveloffspringphenotypic biomarkerpredictive markerreference genomesenescencetelomeretissue culturetranscriptome sequencingtransgene expression
项目摘要
DNA damage accumulates with age in somatic tissues where it contributes to their dysfunction by causing
mutations and cellular senescence. Senescent cells alter tissue microenvironment via secretion of
proinflammatory molecules. DNA damage from endogenous or exogenous sources alone or in combination
with defects in DNA repair pathways often decreases longevity. Long interspersed element-1, L1, an
endogenous retrotransposon, contributes to genomic instability via retrotransposition and the induction of DNA
double-strand breaks. Although endogenous L1 elements are expressed in normal human tissues and cause
DNA damage and cellular senescence, whether L1 affects mammalian life span in vivo is unknown. Among the
500,000 L1 copies present in mammalian genomes only a few L1 loci are capable of causing further DNA
damage. These L1 loci are often polymorphic for their presence in human genomes (pL1s) and are responsible
for the bulk of L1-induced DNA damage. Although some individuals contain two or three times as many of
these pL1 loci than others, the impact of this variation on human life span is not known. Our preliminary data
generated using a transgenic rat model support that a functional L1 transgene increases levels of
proinflammatory markers and shortens average and maximal lifespan in vivo. Our preliminary data also show
that L1 endonuclease cuts telomeric sequences in vitro and may do so in vivo. We hypothesize that
polymorphic L1 loci shorten mammalian lifespan in a dose-dependent manner by causing DNA damage that
induces proinflammatory markers and/or telomere attrition. We will test this hypothesis by using custom
transgenic rats to model variation in the number of functional L1s observed in the human population in order to
study the effect of this variation on longevity in vivo. We will also use DNA samples collected from average and
long-lived (>99 year old) individuals to determine their pL1 content and whether the number of pL1s per
genome correlates with life span. We will use in vitro and tissue culture approaches to determine whether L1
contribution to an increase in SASP markers or telomere attrition could be a plausible mechanism(s) by which
L1 may impact longevity. Combined our findings would provide a currently lacking experimental support for pL1
impact on longevity in vivo and novel mechanisms underlying this effect.
随着年龄的增长,DNA损伤在体细胞组织中积累,通过引起
突变和细胞衰老。衰老细胞通过分泌
促炎分子内源性或外源性DNA损伤单独或联合
DNA修复途径的缺陷通常会降低寿命。长散布元件-1,L1,
内源性反转录转座子,通过反转录转座和诱导DNA
双链断裂虽然内源性L1元件在正常人体组织中表达,
DNA损伤和细胞衰老,L1是否影响哺乳动物体内寿命尚不清楚。中
哺乳动物基因组中存在500,000个L1拷贝,只有少数L1基因座能够引起进一步的DNA
损害这些L1基因座通常因其在人类基因组(pL 1)中的存在而具有多态性,并且负责
L1基因导致的DNA损伤虽然有些个体含有两到三倍于
这些pL 1基因座比其他基因座的基因座我们的初步数据
使用转基因大鼠模型产生的结果支持了功能性L1转基因增加了L1受体的水平。
促炎标志物和缩短体内平均和最大寿命。我们的初步数据还显示
L1核酸内切酶在体外切割端粒序列,并且可以在体内这样做。我们假设
多态性L1基因座通过引起DNA损伤以剂量依赖的方式缩短哺乳动物的寿命,
诱导促炎标志物和/或端粒磨损。我们将通过使用自定义
转基因大鼠,以模拟在人群中观察到的功能性L1数量的变化,
研究这种变异对体内寿命的影响。我们还将使用从平均水平收集的DNA样本,
长寿(>99岁)的人,以确定他们的pL 1含量和是否pL 1的数量,
基因组与寿命相关。我们将使用体外和组织培养的方法来确定是否L1
导致SASP标记物或端粒磨损增加可能是一种合理的机制,
L1可能影响寿命。结合我们的研究结果将提供目前缺乏的实验支持pL 1
对体内寿命的影响以及这种影响的新机制。
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 }}
Victoria Perepelitsa Belancio其他文献
Victoria Perepelitsa Belancio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('Victoria Perepelitsa Belancio', 18)}}的其他基金
Polymorphic L1 transposons as a Genetic Variable Distinguishing Aggressive from Indolent Prostate Cancer
多态性 L1 转座子作为区分侵袭性前列腺癌和惰性前列腺癌的遗传变量
- 批准号:
10260721 - 财政年份:2022
- 资助金额:
$ 33.31万 - 项目类别:
FASEB's Mobile DNA: Evolution, Diversity, and Impact Conference.
FASEB 的移动 DNA:进化、多样性和影响会议。
- 批准号:
10317953 - 财政年份:2021
- 资助金额:
$ 33.31万 - 项目类别:
A Forgotten Connection: Retrotransposon contribution to Alzheimer's Disease
被遗忘的联系:逆转录转座子对阿尔茨海默病的贡献
- 批准号:
10288552 - 财政年份:2018
- 资助金额:
$ 33.31万 - 项目类别:
The impact of LINE-1 retrotransposons on life span, SASP, and telomeres in vivo
LINE-1逆转录转座子对体内寿命、SASP和端粒的影响
- 批准号:
10431860 - 财政年份:2018
- 资助金额:
$ 33.31万 - 项目类别:
The impact of LINE-1 retrotransposons on life span, SASP, and telomeres in vivo
LINE-1逆转录转座子对体内寿命、SASP和端粒的影响
- 批准号:
10212211 - 财政年份:2018
- 资助金额:
$ 33.31万 - 项目类别:
The impact of advanced parental age on genomic instability in offspring associated with retrotransposon-induced DNA damage
高龄父母对逆转录转座子诱导的 DNA 损伤相关后代基因组不稳定性的影响
- 批准号:
9277878 - 财政年份:2017
- 资助金额:
$ 33.31万 - 项目类别:
L 1 element as an inrinsic factor of mammalian aging
L 1 元素作为哺乳动物衰老的内在因素
- 批准号:
8032436 - 财政年份:2008
- 资助金额:
$ 33.31万 - 项目类别:
L 1 element as an inrinsic factor of mammalian aging
L 1 元素作为哺乳动物衰老的内在因素
- 批准号:
7384768 - 财政年份:2008
- 资助金额:
$ 33.31万 - 项目类别:
相似海外基金
Hormone therapy, age of menopause, previous parity, and APOE genotype affect cognition in aging humans.
激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
- 批准号:
495182 - 财政年份:2023
- 资助金额:
$ 33.31万 - 项目类别:
Investigating how alternative splicing processes affect cartilage biology from development to old age
研究选择性剪接过程如何影响从发育到老年的软骨生物学
- 批准号:
2601817 - 财政年份:2021
- 资助金额:
$ 33.31万 - 项目类别:
Studentship
RAPID: Coronavirus Risk Communication: How Age and Communication Format Affect Risk Perception and Behaviors
RAPID:冠状病毒风险沟通:年龄和沟通方式如何影响风险认知和行为
- 批准号:
2029039 - 财政年份:2020
- 资助金额:
$ 33.31万 - 项目类别:
Standard Grant
Neighborhood and Parent Variables Affect Low-Income Preschool Age Child Physical Activity
社区和家长变量影响低收入学龄前儿童的身体活动
- 批准号:
9888417 - 财政年份:2019
- 资助金额:
$ 33.31万 - 项目类别:
The affect of Age related hearing loss for cognitive function
年龄相关性听力损失对认知功能的影响
- 批准号:
17K11318 - 财政年份:2017
- 资助金额:
$ 33.31万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
- 批准号:
9320090 - 财政年份:2017
- 资助金额:
$ 33.31万 - 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
- 批准号:
10166936 - 财政年份:2017
- 资助金额:
$ 33.31万 - 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
- 批准号:
9761593 - 财政年份:2017
- 资助金额:
$ 33.31万 - 项目类别:
How age dependent molecular changes in T follicular helper cells affect their function
滤泡辅助 T 细胞的年龄依赖性分子变化如何影响其功能
- 批准号:
BB/M50306X/1 - 财政年份:2014
- 资助金额:
$ 33.31万 - 项目类别:
Training Grant
Inflamm-aging: What do we know about the effect of inflammation on HIV treatment and disease as we age, and how does this affect our search for a Cure?
炎症衰老:随着年龄的增长,我们对炎症对艾滋病毒治疗和疾病的影响了解多少?这对我们寻找治愈方法有何影响?
- 批准号:
288272 - 财政年份:2013
- 资助金额:
$ 33.31万 - 项目类别:
Miscellaneous Programs