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 senescenceâ€). 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.
