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

该学院早期职业发展（Career）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。众所周知，衰老会在细胞间传播，但这是如何发生的还不清楚。最近观察到，衰老细胞比其他细胞更坚硬，对周围环境的拉力更强，这些特性可能为细胞过程提供重要线索。这个项目的目标是确定刚度和机械力在细胞间传播衰老中的作用。该项目研究两个方面：1)刚度是否促进细胞衰老；2)收缩性细胞是否会引发组织内其他细胞的衰老。这个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，使未来的医学研究成为可能。在研究方面，该项目将为当地学校的孩子们开展活动，强调自我组织的重要概念，或者大型生物系统（如组织）是如何由许多单独的组件（如细胞）形成的。外展活动将鼓励南加州内陆帝国社区的STEM可及性和兴奋性，该社区是少数族裔占多数，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的不可逆退出，具有重要的生理和病理作用，并且已知它在细胞间传播（“旁观者衰老”）。尽管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。本项目将测试机械信号在旁观者衰老中的假设作用，重点关注三个离散问题：1)确定细胞张力增加是否加速衰老；2)判断细胞-细胞粘附张力升高是否引发旁观者衰老；3)确定细胞基质张力增加是否引发旁观者衰老。此外，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和预测框架。这个项目将直接或间接地促进生物工程研究、健康科学和教育。具体来说，发现一种新的衰老诱导机制和非自主繁殖机制将有助于深入了解多个过程，包括：1)生理性衰老如何在伤口愈合中协调；2)病理性衰老如何在衰老和病变组织中传播；3)如何通过机械信号控制细胞行为。该奖项反映了美国国家科学基金会的法定使命，并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，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.