CAREER: Biomechanics and Mechanobiology of Vimentin Intermediate Filaments

This Faculty Early Career Development (CAREER) award will support research to investigate the biomechanical role of vimentin intermediate filaments in cell motility and nuclear stability. Proper cell motility is necessary for wound healing, development, and normal tissue maintenance. Cells must be flexible enough to move and comply with external physical stresses yet strong enough to maintain shape and structural integrity. Thus, while a soft cell nucleus is conducive to cell migration through small pores in tissue, the resulting physical stress (if not mitigated) can lead to nuclear damage and pathogenic conditions. Vimentin is a cytoskeletal component of many migrating cells and is important to nuclear positioning and nuclear stability. However, how vimentin is uniquely able to protect the nucleus is still largely unknown. This research will explore how vimentin enables cells to sense and respond to mechanical stresses. The results of this work shed light on the mechanical and biological signals that control cell migration. This research is complemented by an integrated educational and outreach plan. This plan aims to broaden STEM pathways by attracting and training students through 1) a novel open-access traction force microscopy tool, and 2) a novel course, Public Engagement in Physics and STEM. High school students from Syracuse City School Districts will engage in both outreach activities. The overall research goal of this project is to uncover the biophysical mechanisms by which the cytoskeletal polymer vimentin stabilizes confined cell migration and its role in reinforcing proper nuclear translocation. The study is organized around three objectives: 1) determining the role of vimentin in nuclear shape and deformability, 2) defining how vimentin establishes whole cell polarization and traction stress during 3D migration, and 3) probing vimentin’s role in mechanotransduction pathways associated with cellular response to compressive forces. The findings from this work will provide important new insight into mechanisms of healthy tissue maintenance and disease progression that advance through fundamental cell migration processes. In the longer-term, project outcomes will suggest new strategies to aid cell motility during wound healing as well as disrupt abnormal cell motility and nuclear damage in pathological contexts, such as fibrosis and cancer. 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.