Role of transposon regulation in the negligible senescence of S. mediterranea

转座子调控在地中海链霉菌可忽略的衰老中的作用

• 批准号: 10665794
• 负责人: Josephina C van Wolfswinkel
• 金额: $ 40.19万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665794
• 关键词: ATAC-seq; Acceleration; Address; Adult; Affect; Age; Aging; Animals; Appearance; Attention; Biological Models; Biology of Aging; Cell Differentiation process; Cell Maintenance; Cells; Chemicals; Chromatin; Complex; DNA Transposable Elements; Development; Epigenetic Process; Functional disorder; Genomics; Goals; Health; Healthcare Systems; Human; Life; Longevity; Maintenance; Measures; Mediating; Mobile Genetic Elements; Molecular; Pathway interactions; Phenotype; Planarians; Play; Population; Process; Proteins; RNA; RNA Interference; Regulation; Repression; Resistance; Role; Specimen; Stereotyping; System; Time; Tissue Differentiation; Tissues; Work; adult stem cell; age related; aged; chromatin modification; cost; derepression; driving force; functional decline; genomic locus; healthspan; human stem cells; improved; in vivo; insight; mortality; piRNA; rate of change; regenerative; regenerative tissue; senescence; stem cell aging; stem cell population; stem cells; transcriptome sequencing

PROJECT SUMMARY The progressive decline in the function of adult stem cells is a major factor in the development of age-related conditions. Considering the increasing age of the overall human population, identifying strategies to prolong stem cell health is of major importance. Study of short-lived model systems has identified many potential limiting factors in the maintenance of stem cells, but has been unable to elucidate whether and how stem cell aging could be avoided altogether. We will leverage the negligibly senescent system S. mediterranea to reveal the regulation underlying this animal’s ability to maintain stem cell health seemingly indefinitely. We previously found that planarian stem cells employ a double layer of protection against transposons, whereas the shorter- lived differentiated cells retain only a single defense layer, suggesting that transposons could be a significant threat to stem cell maintenance. Further, loss of transposon silencing leads to rapid lethality in these otherwise long-lived animals. This project focuses on the role of transposon silencing and chromatin compaction in the resistance to aging phenotypes of planarian tissues. We intend to leverage our recent finding of stereotypic age-related markers in planarian differentiated cells to determine the role of various pathways in the progression of planarian aging. Aim 1 of this proposal seeks to elucidate whether changes in transposon levels or in chromatin regulation can change the rate of aging in planarian differentiated tissues. Aim 2 addresses the role of various transposon-related pathways in the indefinite maintenance of planarian stem cells. Aim 3 will determine whether there is a correlation between the lifespan of a planarian tissue type and its control of transposons. Furthermore, the genomic locations of age-related changes in chromatin modifications will be addressed. This project will provide new insights in the workings of a negligibly senescent system. Understanding of the mechanisms it employs in the long-term maintenance of its actively dividing stem cell population will provide new avenues to pursue in search for strategies to extend human stem cell health.

项目概要 成体干细胞功能的逐渐衰退是与年龄相关的疾病发生的一个主要因素 考虑到总人口年龄的增长，确定延长寿命的策略。 干细胞健康非常重要，对短期模型系统的研究已经发现了许多潜力。 干细胞维持的限制因素，但一直无法阐明干细胞是否以及如何维持 我们将利用可忽略不计的衰老系统地中海南海系统来揭示衰老。 我们之前研究过这种动物似乎无限期地维持干细胞健康的能力。 发现涡虫干细胞针对转座子采用双层保护，而较短的 活的分化细胞仅保留单个防御层，这表明转座子可能是一个重要的防御层。 此外，转座子沉默的丧失会导致这些细胞的快速致死。 该项目重点研究转座子沉默和染色质压缩在长寿动物中的作用。 我们打算利用我们最近发现的刻板印象。 涡虫分化细胞中的年龄相关标记，以确定各种途径在 该提案的目标 1 旨在阐明转座子水平是否发生变化。 或在染色质调节中可以改变涡虫分化组织的衰老速度。目标 2 解决了这一问题。 目标 3 将研究各种转座子相关途径在涡虫干细胞无限维持中的作用。 确定涡虫组织类型的寿命与其控制之间是否存在相关性 此外，与年龄相关的染色质修饰变化的基因组位置将是 已解决。 该项目将为可忽略的衰老系统的运作提供新的见解。 它用于长期维持其活跃分裂的干细胞群的机制将提供 寻找延长人类干细胞健康策略的新途径。