Cytoskeletal regulation of single cell migration in complex environments

This Project Grant award of $1.13M from the National Science Foundation (NSF) under the Biological Sciences program (CFDA 47.074), effective September 1, 2025 through August 31, 2028, supports research on cytoskeletal regulation of single cell migration in complex environments. The primary deliverable is fundamental research examining how septin proteins function in cell migration through constrained spaces, with applications to both human immune system cells and Caenorhabditis elegans (nematode worm) migration. The project will develop specialized advanced microscopy techniques to visualize and measure cell movement within dense tissues and three-dimensional environments, addressing significant gaps in understanding cell-cell interactions and migration mechanisms essential for organismal development and cellular function.

Additional project deliverables include workforce development and educational outreach components. The award will support training of undergraduate and graduate students in integrated disciplines spanning biology, optics, and computational analysis methods. Educational modules on cell movement and microscopy will be developed for dissemination to local high schools and incorporated into community outreach activities. Two sub-awards support collaborative research infrastructure: the Marine Biological Laboratory will provide specialized microscopy imaging services, image analysis support, and protocol development utilizing home-built microscopes; and Siena College will recruit and train 2-3 undergraduate students annually through hands-on laboratory modules in microscopy, cell biology, and image analysis, with student participants presenting findings at regional and national scientific conferences.

Abstract

This project will provide significant new information about how single cells are able to squeeze through tight spaces, by understanding how the scaffolds that support cell shape are remodeled and coordinated. Cells come in all shapes and sizes and often need to move through constricted spaces to perform their functions. The mechanisms that allow small cells to move quickly and nimbly can be conserved between different organisms, from the smallest nematode worms to humans. Specifically, this project will focus on proteins named septins, which can act like a girder to protect cells as they crawl through constrained environments. The primary aim of this project is to understand how evolutionarily conserved septin proteins function similarly or differently under varied conditions, including in the human immune system and in migrating worm cells. Septin protein function will be studied, in part, by developing specialized microscopy techniques that to allow observing cells moving within dense tissues and tight environments. This project will also train undergraduate and graduate students, and is designed to provide specialized training in biology, optics, and computational analysis approaches. In order to share discoveries and inspire the broader community, modules on cell movement and microscopy will be made available to local high schools and incorporated into outreach activities. Cell migration is critical for organismal development and cellular function. Despite the overwhelming importance of cell migration, much remains to be understood in how cell-cell interactions in complex and 3-dimensional tissue environments shape cell migration and the cellular functions that are regulated by cell migration. The difficulty of obtaining this knowledge is the result of the inherent biological and technical complexity of models needed to visualize and measure these processes. An additional challenge in the field is the ongoing specialization of cell biology, microscopy, and image analysis fields, which can act as a barrier for learners who are motivated to contribute to areas of research found at the intersection of these fields but lack uniform training across all these highly specialized areas of research. The overall objective of this project is to define how septin-based cytoskeletal scaffolds regulate the migration of single cells in varied tissue environments. The research to be performed includes the study of novel cell biological mechanisms, the development of tools for imaging and analysis, and the design of best practices for educating learners. The specific objectives of this project are to: 1) define conserved and unique functions and architecture of septin proteins in 3-dimensional cell migration in complex microenvironments; 2) advance the use of light microscopy to visualize complex events within physiological systems; and 3) generate best practices for the effective teaching of multidisciplinary approaches contained in this project to learners from a range of backgrounds, expertise, and levels of training. This project is funded by the NSF/BIO/MCB cell dynamics & function program. 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.- subawards are planned for this award.