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.

该奖项全部或部分根据2021年美国救援计划法案（公法117-2）资助。现代人类相对于非人类灵长类动物寿命更长，并且经常在高龄时保持活跃。然而，人类生物学和衰老时间差异的演变还没有得到很好的理解。这篇博士论文使用基于实验室的细胞实验来识别人类基因组中充当调节衰老的“开关”的元素。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衰老和生命史进化的理解。对细胞衰老过程的关注也可能为其他基础和临床研究社区提供信息。研究人员与博物馆和教学中心合作，开发展览和在线学习材料，以更广泛地突出人类衰老和进化理论的进化研究。该项目包括对本科生（包括那些来自STEM领域代表性不足的学生）进行生物人类学和相关领域的职业培训。人类相对于黑猩猩寿命延长的观察表明，衰老的生物机制存在进化差异。有一种假说认为，在人属的进化过程中，细胞衰老的速度可能有所减缓。在这个项目中，研究人员使用人类膝关节作为检查组织衰退和功能障碍的模型系统。进行实验以产生功能失调的膝关节软骨细胞，使用下一代测序测定来表征细胞调控网络中的变化，包括蛋白质的表达以及编码这些蛋白质的基因是如何被调控的，这定义了衰老过程。然后将该实验数据集与计算遗传分析相结合，以了解人类序列进化在修改这些网络中的作用以及可能导致的组织衰退的后果。这些公开的数据集可以作为生物人类学，衰老，基因调控和联合生物学领域研究的重要资源。鉴于缺乏关节组织细胞的综合数据集，特别是在衰老和细胞衰老的背景下，这项研究对生物医学界和研究与年龄相关的关节疾病（如骨关节炎）的人具有潜在的兴趣。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的知识价值和更广泛的影响审查标准进行评估来支持。