NSF Award
2024182
All cells must sense and respond to force, otherwise physical forces would tear them apart. However, it is still poorly understood how cells turn a purely physical stimulus, like force, into a biochemical signal. One potential mechanism involves the giant protein obscurin. One end of this protein binds to the cell membrane and the other end binds the cytoskeleton. The middle of the protein acts like a rope in that it is able to change shape and elongate without requiring any major energy contribution. But if obscurin is stretched too far, it begins to act like a spring, gradually resisting additional stretch. Obscurin also contains enzymatically active regions that are thought to ‘turn on’ when it is stretched. This project tests the model that obscurin is a signal transducing mechano-molecule that senses and responds to the physical force of stretch experienced by living cells. This research will provide insights into how cells ‘feel’ force, how they react to this force on a molecular level, and how this phenomenon informs tissue growth. The Broader Impacts of this project integrate a strong undergraduate science education program and community outreach. In collaboration with the capstone class of James Madison University’s engineering department, interactive machines will be developed and built that teach fundamental concepts of molecular biology. These machines will be displayed at local county fairs, bringing science and engineering concepts to a population that is often excluded from other science outreach efforts.<br/> <br/><br/>This project addresses a novel mechanism of mechano-transduction between membranes and the cytoskeleton of the cell by focusing on the protein obscurin, a putative stretch sensor. This research will determine whether obscurin is under tension within the cell. It will also determine the extent to which its localization and signaling are directly related to the forces experienced by the cell. Third, this work will determine whether obscurin localization influences the motility of sheets of cells in response to the force they experience. To answer these questions, this project will use a combination of FRET microscopy, fluorescent tension sensors, tissue ablation techniques, cell biological approaches, and computer modelling. The data obtained from these experiments will be used to create a predictive model of cell motility. Together, these experiments will reveal obscurin’s role in cellular mechanosensation. Because obscurin is found in multiple cell types, this basic science work is expected to have impact on a broad range of more specific topics, including embryonic development, cell invasiveness, endothelial cell biology, muscle biology, and cardiomyocytes.<br/><br/>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.
