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：
10212211
负责人：
Victoria Perepelitsa Belancio
金额：
$ 33.44万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
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：
https://reporter.nih.gov/project-details/10212211
关键词：
Adult Affect Age Animal Model Attenuated Biological Biological Assay Cancer Patient Cell Aging Cell physiology Cells Centenarian Cultured Cells Custom DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Pathway Data Defect Deterioration Development Disease Dose Elements Functional disorder Future Gene Frequency Genetic Genetic Markers Genome Genomic DNA Genomic Instability Genomics Goals Health Heritability Human Human Genome In Vitro Individual Indolent Interleukin-6 Lead Length Location Long Interspersed Elements Longevity Lung Malignant neoplasm of prostate Measurable Messenger RNA Methods Modeling Mutation Normal tissue morphology Organ Phenotype Population Rat Transgene Rattus Reporting Retrotransposition Retrotransposon Risk Risk Factors Sampling Somatic Cell Source Specificity System Telomerase Telomere Shortening Testing Testis Time Tissues Transgenes Transgenic Organisms Variant cohort endonuclease genetic element genetic testing genome wide association study human tissue in vivo mRNA Expression mammalian genome middle age mutant novel offspring phenotypic biomarker predictive marker reference genome senescence telomere tissue culture transcriptome sequencing transgene expression

Adult Affect Age Animal Model Attenuated Biological Biological Assay Cancer Patient Cell Aging Cell physiology Cells Centenarian Cultured Cells Custom DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Pathway Data Defect Deterioration Development Disease Dose Elements Functional disorder Future Gene Frequency Genetic Genetic Markers Genome Genomic DNA Genomic Instability Genomics Goals Health Heritability Human Human Genome In Vitro Individual Indolent Interleukin-6 Lead Length Location Long Interspersed Elements Longevity Lung Malignant neoplasm of prostate Measurable Messenger RNA Methods Modeling Mutation Normal tissue morphology Organ Phenotype Population Rat Transgene Rattus Reporting Retrotransposition Retrotransposon Risk Risk Factors Sampling Somatic Cell Source Specificity System Telomerase Telomere Shortening Testing Testis Time Tissues Transgenes Transgenic Organisms Variant cohort endonuclease genetic element genetic testing genome wide association study human tissue in vivo mRNA Expression mammalian genome middle age mutant novel offspring phenotypic biomarker predictive marker reference genome senescence telomere tissue culture transcriptome sequencing transgene expression

展开

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.

DNA损伤在体细胞组织中随着年龄的增长而累积，该组织会导致其功能障碍。突变和细胞衰老。衰老细胞通过分泌改变组织微环境促炎分子。单独或组合内源或外源性来源的DNA损伤随着DNA修复途径的缺陷，通常会降低寿命。长散布的元素-1，l1，一个内源性逆转座子，通过逆转录和DNA诱导导致基因组不稳定性双链断裂。尽管内源性L1元素在正常的人体组织中表达，并导致 DNA损伤和细胞衰老，L1是否影响体内哺乳动物生命跨度是未知的。在哺乳动物基因组中存在的500,000 L1副本只有几个L1基因座能够引起进一步的DNA 损害。这些L1基因座通常对于它们在人类基因组（PL1）中的存在通常是多态性的，并且是负责的对于大部分L1诱导的DNA损伤。尽管有些人包含的两到三倍这些PL1基因座比其他基因座，这种变异对人类寿命的影响尚不清楚。我们的初步数据使用转基因大鼠模型支持功能性L1转基因会增加的水平促炎标记并缩短体内平均水平和最大寿命。我们的初步数据也显示该L1核酸酶在体外切割端粒序列，并可能在体内进行。我们假设这一点多态L1基因座以剂量依赖性的方式缩短了哺乳动物的寿命，从而导致DNA损伤诱导促炎标记和/或端粒损耗。我们将使用自定义检验该假设转基因大鼠以模拟在人口中观察到的功能性L1数量的变化，以便为了研究这种变异对体内寿命的影响。我们还将使用平均收集的DNA样品，长寿（> 99岁）的人确定其PL1含量以及是否pl1的数量基因组与寿命相关。我们将使用体外和组织培养方法来确定L1是否对SASP标记或端粒损耗增加的贡献可能是一种合理的机制 L1可能会影响寿命。结合我们的发现将为PL1提供目前缺乏实验支持对体内寿命的影响和这种效果的基础的新型机制。