Aging Effect on Genome Maintenance during Hepatocyte Regeneration

衰老对肝细胞再生过程中基因组维持的影响

• 批准号: 9315681
• 负责人: ROBERT Y TSAI
• 金额: $ 18.56万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9315681
• 关键词: Adult; Affect; Age; Aging; Aging-Related Process; Automobile Driving; Binding; Binding Sites; CCAAT-Enhancer-Binding Protein-alpha; Cell Cycle; DNA Damage; Data; Disease; Down-Regulation; Exhibits; Genetic Transcription; Genome; Genome Stability; Goals; Growth; Health; Hepatocyte; Homeostasis; Injury; Knock-in Mouse; Liver; Liver Regeneration; Maintenance; Mediating; Mus; Natural regeneration; Organ; Outcome; Pathway interactions; Phenotype; Play; Postoperative Period; Predisposition; Premature aging syndrome; Proteins; Recovery; Research; Rest; Role; Signal Pathway; Stem cells; Testing; Tissues; age effect; age related; aged; base; cancer cell; clinically significant; design; genome integrity; improved; in vivo; liver transplantation; novel; older patient; overexpression; programs; promoter; regenerative; self-renewal; senescence; stem

PROJECT SUMMARY Liver is a vital organ with a unique capability to regenerate after injuries via a dual mechanism. This ability, however, is significantly compromised by aging. Most studies that investigate the aging effect on liver regeneration focus on the signaling pathways that drive the cell cycle reentry and growth of regenerating hepatocytes. A missing but critical piece of the puzzle, as a recent study from my lab has shown, is the mechanism that maintains the regenerative potential of hepatocytes by safeguarding them from replication- induced DNA damage. The key driver of this program is a stem and cancer cell-enriched protein, nucleostemin (NS). To date, it remains unclear whether the NS pathway plays a determinant role in the age-associated decline of liver regeneration and how its expression and activity is regulated in the liver during the aging process. To solve the puzzle of how aging affects liver regeneration, there is a critical need to determine the mechanism by which aging regulates NS function in the liver. My long-term goal is to determine how self- renewal programs contribute to the regeneration and homeostasis of adult tissues during the aging process. The objective of this proposal is to determine the role of NS in age-associated decline of liver regeneration and how its expression is down-regulated in regenerating hepatocytes during the aging process. Our central hypothesis states that age-related NS down-regulation via a C/EBPα-controlled mechanism sets a threshold (determinant) level that limits the regenerative potential of the liver. This hypothesis is formulated based on: 1) NS is up-regulated on or before the cell cycle reentry of regenerating hepatocytes and serves an essential role in protecting them from replicative DNA damage; 2) NS deletion compromises liver regeneration after injuries; 3) the levels of NS and Ki67 are both down-regulated in aged livers under the resting and regenerating conditions compared to young livers; 4) NS promoter contains cognate C/EBPα-binding sites, and its transcriptional activity is inhibited by C/EBPα; and 5) C/EBPα is known to inhibit the regeneration of aged livers. To test our hypothesis, two specific aims will be pursued. Aim 1 will determine the role of NS in age- associated decline of liver regeneration. Aim 2 will determine the transcriptional mechanism that drives NS down-regulation during liver aging. At the completion, we expect to have determined the importance of NS in setting a threshold level that caps the regenerative potential of aged livers, and the transcriptional program that drives the down-regulation of NS during the aging process. These outcomes will fill the need to understand the molecules that underpin the age-related decline of liver regeneration and the mechanisms that may precipitate or alleviate the effect of aging on liver regeneration. A successful completion of this proposal will therefore have a direct impact on resolving the health issues caused by age-dependent decline of liver regeneration and a broad impact on advancing research on the aging effect on the regeneration of other adult tissues.

项目摘要 肝脏是一个重要的器官，具有通过双重机制在受伤后再生的独特能力。这个能力， 但是，老化会大大损害。大多数研究对肝脏衰老影响的研究 再生重点放在驱动细胞周期再入和再生生长的信号通路上 肝细胞。正如我的实验室的最新研究所表明的那样 通过保护肝细胞免受复制 - 诱导DNA损伤。该程序的主要驱动力是茎和癌细胞富集的蛋白质核抑素 （NS）。迄今为止，尚不清楚NS途径是否在与年龄相关的 肝脏再生的下降及其在衰老期间如何调节其表达和活性 过程。为了解决衰老如何影响肝脏再生的难题，确定的迫切需要 衰老调节NS功能在肝脏中的机制。我的长期目标是确定如何自我 在老化过程中，更新计划有助于成人组织的再生和体内稳态。 该提案的目的是确定NS在与年龄相关的肝脏再生下降中的作用和 在衰老过程中，其在再生肝细胞中如何下调其表达。我们的中心 假设指出，与年龄相关的NS通过C/EBPα控制机制下调为阈值 （决定因素）限制肝脏再生潜力的水平。该假设是基于以下方式提出的：1） NS在再生肝细胞的细胞周期再入院时被上调，并发挥至关重要的作用 保护它们免受复制DNA损伤； 2）NS缺失会损害肝脏再生； 3）在静止和再生下，NS和KI67的水平都下调了 与年轻生活相比； 4）NS启动子包含同源C/EBPα结合位点及其 C/EBPα抑制转录活性； 5）已知C/EBPα可以抑制老化的再生 肝。为了检验我们的假设，将追求两个具体的目标。 AIM 1将确定NS在年龄中的作用 - 肝脏再生的相关下降。 AIM 2将确定驱动NS的转录机制 肝老化期间的下调。完成后，我们希望确定NS在 设置阈值水平，以限制老年生的再生潜力，以及转录计划 在老化过程中驱动NS的下调。这些结果将满足了解 支撑肝脏再生与年龄相关的分子和可能沉淀的机制 或减轻衰老对肝脏再生的影响。因此，该提案的成功完成将 直接影响解决肝脏再生年龄下降和 对衰老对其他成年组织再生的衰老影响的广泛影响。

项目成果

Epigenome-wide analysis of aging effects on liver regeneration.

• DOI: 10.1186/s12915-023-01533-1
• 发表时间: 2023-02-13
• 期刊: BMC BIOLOGY
• 影响因子: 5.4
• 作者: Wang, Junying;Zhang, Wen;Liu, Xiaoqin;Kim, Minjee;Zhang, Ke;Tsai, Robert Y. L.
• 通讯作者: Tsai, Robert Y. L.