Doctoral Dissertation Research: Cellular Senescence in Human Age-Related Mortality and Lifespan

博士论文研究：细胞衰老与人类年龄相关的死亡率和寿命

• 批准号: 2116277
• 负责人: Terence Capellini
• 金额: $ 3.38万
• 依托单位: Harvard University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2116277&HistoricalAwards=false
• 关键词: Doctoral; Dissertation; Research; Cellular; Senescence

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2). Modern humans are longer-lived relative to non-human primates and often remain active at advanced ages. However, the evolution of differences in the biology and timing of aging in humans is not well understood. This doctoral dissertation uses laboratory-based cellular experiments to identify elements of the human genome that act as ‘switches’ to regulate aging. By defining how the genetic sequences of these switches have evolved in humans, the investigators add to the current understanding of human senescence and life history evolution. The focus on cellular aging processes also may inform other basic and clinical research communities. In conjunction with museums and pedagogical centers, the researchers develop exhibits and online learning materials to highlight this research on the evolution of human aging and evolutionary theory more broadly. The project involves the training of undergraduate students, including those from underrepresented backgrounds in STEM, for careers in biological anthropology and related fields.The observation of elongated lifespan in humans relative to chimpanzees suggests evolutionary differences in the biological mechanisms of aging. One hypothesis is that during the evolution of the genus Homo there may have been deceleration in cellular senescence. In this project, the researchers use the human knee joint as a model system for examining tissue decline and dysfunction. Experiments are performed to generate dysfunctional knee cartilage cells, using next-generation sequencing assays to characterize shifts in cell regulatory networks, both in the expression of proteins and how the genes encoding these proteins are regulated, that define the senescence process. This experimental dataset is then combined with computational genetic analyses to understand the role of human sequence evolution in modifying these networks and the consequences to tissue decline that may have resulted. These publicly-available datasets can serve as an important resource for research in the fields of biological anthropology, aging, gene regulation, and joint biology. Given the dearth of comprehensive datasets for joint tissue cells, particularly in the context of aging and cellular senescence, this research is of potential interest to the biomedical community and those studying age-related joint diseases such as osteoarthritis.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该奖项是根据2021年《美国救援计划法》（公法117-2）全部或部分资助的。相对于非人类隐私，现代人类的寿命更长，并且经常在高级时代保持活跃。但是，人类衰老的生物学和时机差异的演变尚不清楚。该博士学位论文使用基于实验室的细胞实验来识别人类基因组的元素，这些元素是调节衰老的“开关”。通过定义这些开关的遗传序列如何在人类中进化，研究人员增加了对人类感应和生活历史进化的当前理解。对细胞衰老过程的关注也可能为其他基本和临床研究社区提供信息。研究人员与博物馆和教学中心一起开发了展览和在线学习材料，以更广泛地强调有关人类衰老和进化论的演变的研究。该项目涉及对本科生的培训，包括STEM中代表性不足的背景的培训，用于生物人类学和相关领域的职业。相对于黑猩猩，人类对延长寿命的观察表明，衰老的生物学机制的进化差异。一个假设是，在同性恋属的演变过程中，细胞感应中可能存在减速。在这个项目中，研究人员使用人膝关节作为检查组织下降和功能障碍的模型系统。使用下一代测序测定法进行实验以产生功能失调的膝关节软骨细胞，以表征细胞调节网络中的变化，包括蛋白质的表达以及编码这些蛋白质的基因如何受到调节，从而定义了敏感过程。然后将该实验数据集与计算遗传分析相结合，以了解人类序列演变在修改这些网络中的作用以及可能导致的组织下降的后果。这些公共可用的数据集可以作为生物人类学，衰老，基因调节和联合生物学领域研究的重要资源。鉴于关节组织细胞的全面数据集死亡，尤其是在衰老和细胞感应的背景下，这项研究具有生物医学界的潜在感兴趣，以及研究与年龄相关的关节疾病（如骨关节炎）的潜在感兴趣。这奖反映了NSF的法定任务，并通过使用基金会的智力效果评估了支持，并通过评估诚实地表达了支持。