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.

项目摘要 成体干细胞功能的进行性下降是年龄相关性干细胞发育的主要因素。 条件考虑到总人口年龄的增长，确定延长寿命的策略 干细胞健康至关重要。对短寿命模型系统的研究已经确定了许多潜在的 限制因素在维持干细胞，但一直无法阐明是否以及如何干细胞 老化是可以完全避免的。我们将利用可忽略的衰老系统S。Mediterranea显示 这种动物维持干细胞健康的能力似乎是无限期的。我们之前 发现真涡虫干细胞对转座子有双层保护，而短- 活的分化细胞只保留一个单一的防御层，这表明转座子可能是一个重要的基因。 对干细胞维持的威胁。此外，转座子沉默的丧失导致这些其他基因中的快速致死性。 长寿的动物该项目的重点是转座子沉默和染色质压缩在细胞凋亡中的作用。 对真涡虫组织的老化表型的抵抗力。我们打算利用我们最近发现的刻板印象 年龄相关的标志物，以确定各种途径的作用， Planarian老化的进展。本提案的目标1旨在阐明转座子水平的变化是否 或在染色质调节中的作用可以改变真涡虫分化组织的衰老速率。目标2针对 各种转座子相关途径在无限期维持真涡虫干细胞中的作用。目标3将 确定是否有一个真涡虫组织类型的寿命和它的控制之间的相关性 转座子此外，年龄相关的染色质修饰变化的基因组位置将是 处理。 这个项目将提供一个可忽略的衰老系统的运作新的见解。理解 它在长期维持其活跃分裂的干细胞群体中所采用的机制将提供 在寻求延长人类干细胞健康的战略方面寻求新的途径。