Transposable elements as drivers of normal and accelerated aging in Vertebrates

转座因子作为脊椎动物正常和加速衰老的驱动因素

基本信息

批准号：
9794215
负责人：
Berenice Anath Benayoun
金额：
$ 25.27万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9794215
关键词：
African Age Aging Aneuploidy Animal Model Antibodies Biological Bypass Cell Separation Cells Cerebellum Communities DNA DNA Damage DNA Insertion Elements DNA Repair Enzymes DNA Transposable Elements Data Set Development Disease Distant Economic Burden Elements Event Family Fishes Gene Expression Regulation Generations Genes Genetic Genetic Variation Genome Genome Stability Genomic Instability Genomics Health Heart Heterochromatin Human Inbreeding Induced Mutation Intervention Jumping Genes Killifishes Laboratories Lead Life Link Liver Longevity Maize Mammals Maps Mass Spectrum Analysis Mobile Genetic Elements Modeling Molecular Mus Mutation Neurodegenerative Disorders Nucleotides Organ Organism Parasites Paste substance Patients Pattern Pharmacology Phenotype Physiological Process Proteins Proteomics Protocols documentation RNA Regulation Repetitive Sequence Reporter Repression Research Research Personnel Retrotransposon Specificity Study models System Taxonomy Testing Therapeutic Intervention Tissues Transgenic Animals Transgenic Organisms Vertebrates Work Yeasts age related aged cell type derepression epigenomics functional decline improved in vivo juvenile animal pathological aging repaired single-cell RNA sequencing therapeutic target tool transcriptome transcriptome sequencing transposon/insertion element

项目摘要

A key hallmark of aging is an overall increase in genomic instability. Accumulating evidence has revealed widespread reactivation of transposable elements (TE) during aging across taxonomically-distant model organisms. Yet, the relationship between this aberrant reactivation and age-related functional decline is largely unknown, at the cellular, organ and organism levels. We hypothesize that the progressive loss of transposon repression contributes to the widespread age-related functional decline at the organismal level. The African turquoise killifish (Nothobranchius furzeri), an emerging naturally short-lived vertebrate model organism, provides a unique opportunity to investigate this link, and the investigators have previously developed a powerful genome-to-phenotype toolkit for this species. In this proposal, we propose to leverage the African turquoise killifish as a tractable short-lived model organism to rapidly interrogate the molecular and organismal impact of increased TE activity on vertebrate aging in vivo. To test our hypothesis, we propose (i) to characterize the repetitive element landscape in the genome of the African turquoise killifish and TE activation patterns, and (ii) to explore the impact of conserved changes in TE regulation with aging and age-related disease on the aging process. The completion of this project will advance the understanding of vertebrate aging. Ultimately, these findings will help define therapeutic targets for development of new treatments for age-associated diseases that have a heavy economic burden, and more importantly, cause extreme suffering to patients and their families.

衰老的一个关键标志是基因组不稳定性的总体增加。积累的证据已经揭示衰老过程中转座因子（TE）在分类学上遥远的模型中广泛重新激活有机体。然而，这种异常的重新激活与年龄相关的功能衰退之间的关系在很大程度上是在细胞、器官和生物体水平上未知。我们假设转座子的逐渐丧失压抑导致机体水平上与年龄相关的广泛功能衰退。非洲人绿松石鳉鱼（Nothobranchius Furzeri），一种新兴的自然短命脊椎动物模式生物，提供了一个独特的机会来研究这种联系，并且研究人员之前已经开发了一种该物种强大的基因组到表型工具包。在本提案中，我们建议利用非洲绿松石鳉鱼作为一种易驯化的短命模式生物，可以快速询问分子和 TE 活性增加对脊椎动物体内衰老的影响。为了检验我们的假设，我们建议（i）表征基因组中的重复元素景观非洲绿松石鳉鱼和 TE 激活模式，以及 (ii) 探索保守变化的影响 TE对衰老和年龄相关疾病对衰老过程的调节作用。该项目的完成将促进对脊椎动物衰老的理解。最终，这些发现将有助于确定治疗目标开发针对经济负担沉重的与年龄相关的疾病的新疗法等更重要的是，给患者及其家属带来极大的痛苦。