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

职业：机械老化：了解驱动细胞衰老的机械力

• 批准号: 2046093
• 负责人: Joshua Morgan
• 金额: $ 51.46万
• 依托单位: University of California-Riverside
• 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: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2046093&HistoricalAwards=false
• 关键词: CAREER; Mechanoaging; Understanding; Mechanical; Forces

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.

这个教师早期职业发展（CAREER）奖将研究组织力学在细胞衰老中的作用。细胞衰老，定义为细胞不能再分裂，是伤口愈合，癌症和衰老的重要组成部分。衰老是已知的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。最近已经观察到，衰老细胞比其他细胞更僵硬，对周围环境的拉动更强烈，这些属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。本项目调查以下两方面：1）硬度是否促进细胞衰老;以及2）收缩细胞是否触发组织内其他细胞的衰老。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力来实现未来的医学研究。与研究方面平行，该项目将为当地学童开展活动，突出自我组织的重要概念，或大型生物系统（如组织）如何由许多单个组件（如细胞）形成。 外展计划将鼓励STEM在南加州的内陆帝国社区的可及性和兴奋，这是大多数少数民族和严重的医疗服务不足。这个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，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，并且已知其从细胞扩散到细胞（“旁观者衰老”）。尽管对衰老的分子途径有着严格的理解，但我们对机械信号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，重点是三个离散的问题：1）确定增加的细胞张力是否加速进入衰老; 2）确定增加的细胞-细胞粘附张力是否触发旁观者衰老; 3）确定增加的细胞-基质张力是否触发旁观者衰老。此外，该项目的方法利用互补的实验和计算建模方法，使创建一个描述性和预测性的框架衰老机械生物学。该项目将直接和间接地促进生物工程研究，健康科学和教育。具体而言，衰老诱导和非自主传播的新机制的鉴定将提供对多个过程的洞察，包括1）生理衰老如何在伤口愈合中协调; 2）病理衰老如何通过老化和患病组织传播;和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，并被认为值得支持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。