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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：
Victoria Perepelitsa Belancio
金额：
$ 33.31万
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/9764227
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 Genetic screening method 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 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

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。