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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