CAREER: Mechanoaging: Understanding the Mechanical Forces that Drive Cellular Aging

这个学院早期职业发展奖将研究组织力学在细胞衰老中的作用。细胞衰老，定义为细胞不再分裂，是伤口愈合、癌症和衰老的重要组成部分。已知衰老会从一个细胞传播到另一个细胞，但这是如何发生的还不清楚。最近观察到，衰老的细胞比其他细胞更坚硬，对周围环境的拉力更强，这些属性可能为细胞过程提供必要的线索。这个项目的目标是确定僵硬和机械力在将衰老从细胞传播到细胞中的作用。该项目研究了两个方面：1)僵硬是否会促进细胞衰老；2)收缩细胞是否会在组织内的其他细胞中引发衰老。该项目的结果最终将通过提供对调节伤口愈合、癌症和衰老的衰老人群的洞察，最终使未来的医学研究成为可能。与研究方面平行，该项目将为当地学童开展活动，强调自我组织的重要概念，或大型生物系统(如组织)如何由许多单独的组成部分(如细胞)形成。外展计划将在南加州内陆帝国社区鼓励STEM的可及性和兴奋感，该社区是少数族裔，医疗服务严重不足。该项目将回答有关机械信号在细胞衰老中的作用的基本问题。细胞衰老被定义为细胞周期不可逆转的退出，具有重要的生理和病理作用，并被认为是从一个细胞传播到另一个细胞(旁观者衰老)。尽管我们对衰老的分子途径有严格的了解，但我们对机械信号的作用的数据相对较少。该项目将测试机械信号在旁观者衰老中的假设作用，重点放在三个离散的问题上：1)确定细胞张力增加是否加速进入衰老；2)确定细胞-细胞黏附张力增加是否触发旁观者衰老；以及3)确定细胞-基质张力增加是否触发旁观者衰老。此外，该项目方法利用互补的实验和计算建模方法，能够创建衰老机械生物学的描述性和预测性框架。该项目将直接和间接地为生物工程研究、健康科学和教育做出贡献。具体地说，识别衰老诱导和非自主繁殖的新机制将提供对多种过程的洞察，包括1)生理性衰老如何在伤口愈合中协调；2)病理性衰老如何通过衰老和患病组织传播；以及3)如何通过机械信号控制细胞行为。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

This Faculty Early Career Development (CAREER) award will study the role of tissue mechanics in cellular senescence. Cellular senescence, defined as when cells can no longer divide, is an important component of wound healing, cancer, and aging. Senescence is known to spread from cell to cell, but how this occurs is not understood. It has been recently observed that senescent cells are stiffer and pull more strongly on their surroundings than other cells, and these attributes may provide essential clues to cellular processes. The goal of this project is to identify the role of stiffness and mechanical force in spreading senescence from cell to cell. This project investigates both: 1) whether stiffness encourages cellular senescence; and 2) whether contractile cells trigger senescence in other cells within a tissue. The results of this project will eventually enable future medical research by providing insight into senescent populations that regulate wound healing, cancer, and aging. Parallel to the research aspect, this project will develop activities for local school children highlighting the important concept of self-organization, or how large biological systems (like tissues) are formed from many individual components (like cells). The outreach initiatives will encourage STEM accessibility and excitement in the Inland Empire community of Southern California, which is majority-minority and critically medically underserved.This project will answer fundamental questions regarding the role of mechanical signaling in cellular senescence. Cellular senescence, defined as the irreversible exit of the cell cycle, has important physiological and pathological roles, and it is known to spread from cell to cell (“bystander senescence”). Despite rigorous understanding of the molecular pathways of senescence, we have relatively little data on the role of mechanical signaling. This project will test a hypothetical role for mechanical signaling in bystander senescence, focusing on three discrete questions: 1) Determine whether increased cellular tension accelerates the entry into senescence; 2) Determine whether increased cell-cell adhesion tension triggers bystander senescence; and 3) Determine whether increased cell-matrix tension triggers bystander senescence. Further, the project approach utilizes complementary experimental and computational modeling methods, enabling creation of a descriptive and predictive framework for senescent mechanobiology. This project will directly and indirectly contribute to bioengineering research, health sciences, and education. Specifically, identification of a novel mechanism of senescence induction and non-autonomous propagation will provide insight into multiple processes, including 1) how physiological senescence is coordinated in wound healing; 2) how pathological senescence propagates through aged and diseased tissue; and 3) how cellular behavior can be controlled through mechanical signaling.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.