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.

项目总结 肝脏是一个重要的器官，具有独特的损伤后通过双重机制再生的能力。这种能力， 然而，随着年龄的增长，这一点会受到严重影响。研究衰老对肝脏影响的研究最多 再生侧重于驱动细胞周期重入和再生生长的信号通路 肝细胞。正如我的实验室最近的一项研究所表明的那样，这个拼图中缺失但关键的一块是 通过保护肝细胞免受复制来保持其再生潜力的机制- 诱导DNA损伤。这一计划的关键驱动力是一种富含干细胞和癌细胞的蛋白质--核干素 (NS)。到目前为止，NS通路是否在年龄相关的 衰老过程中肝脏再生功能的衰退及其表达和活性的调节 进程。为了解决衰老如何影响肝脏再生的难题，迫切需要确定 衰老调节肝脏NS功能的机制。我的长期目标是确定如何自我 在衰老过程中，更新计划有助于成人组织的再生和动态平衡。 这项建议的目的是确定NS在年龄相关性肝再生和肝再生功能衰退中的作用。 其在衰老过程中再生肝细胞中的表达如何下调。我们的中央 假说表明，年龄相关的NS通过C/EBPα控制机制下调设定了阈值 (决定因素)限制肝脏再生潜力的水平。这一假设是建立在以下基础上的：1) NS在再生肝细胞重新进入细胞周期时或之前被上调，并发挥重要作用 在保护它们免受复制的DNA损伤方面；2)NS缺失损害了损伤后的肝再生； 3)老年肝脏在静息状态和再生状态下，NS和Ki67水平均下调 4)NS启动子含有同源的C/EBPα结合位点，其 转录活性被C/eBPα抑制；5)已知C/eBPα抑制老年人的再生 肝脏。为了验证我们的假设，我们将追求两个具体目标。目标1将确定NS在年龄中的作用- 合并肝再生功能减退。目标2将确定驱动NS的转录机制 在肝脏老化过程中下调表达。在完成时，我们希望确定NS在 设定一个阈值水平，限制老化肝脏的再生潜力，转录程序 在衰老过程中驱动NS的下调。这些结果将满足理解 支持与年龄相关的肝再生衰退的分子及其可能的沉淀机制 或减轻衰老对肝脏再生的影响。因此，这项提案的成功完成将 对解决因年龄相关性肝再生功能减退而引起的健康问题有直接影响 对推进衰老对其他成人组织再生影响的研究具有广泛的影响。

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.