Cytoskeletal regulation of single cell migration in complex environments

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.