This project will increase our understanding of how cells coordinate their structure and their growth. Cells, which are the fundamental unit of life, have a defined shape built by a set of internal structural proteins known as the cytoskeleton. Cells also grow, divide, and sense their mechanical environment. Some of these functions are also dependent on cytoskeletal proteins. In this project, the researches will examine the mechanism by which spectrin, a giant cytoskeletal protein, performs its functions in cell growth, division and mechano-sensing. Associated with this research, the principle investigator and her team will engage in outreach activities that promote STEM careers including leading an effort in the College of Science to bring a mobile science classroom to central/eastern Pennsylvania and working with a local science museum. These activities will provide high-impact STEM experiences to K-12 students, as well as bring teacher professional development to rural and inner-city areas. The principle investigator’s lab will also participate in programs that promote women, minority and LGBTQ+ undergraduate participation in research, and bring research projects into undergraduate teaching laboratories, enhancing undergraduate education.
Cellular growth must be integrated with the mechanical properties of cellular structures. Spectrins are giant cytoskeletal proteins with two contrasting activities. They are best known for their ability to form fishing net-like structural networks with F actin at the cell cortex that can undergo mechanical stretching. However, spectrins have recently also been shown to modulate protein trafficking in the endosome system. The molecular regulation that balances these two activities is unknown. Through the study of Beta-H-spectrin in epithelial cells of Drosophila melanogaster, this project will test two competing hypotheses to elucidate the molecular mechanisms by which spectrins coordinate mechanosensing and growth control in the cell. One approach will test the hypothesis that tension in the spectrin network plays a role in the relocation of the membrane protein Crumbs and in its control of the growth-inhibiting Hippo pathway. The second approach tests the hypothesis that spectrin networking contributes to the regulation of Crumbs/Hippo control of cell growth in endosomes. The project will use advanced STORM imaging and protein biochemistry to determine the geometry of the spectrin network and the extent to which it is stretched by changes in Myosin II-generated tension. Protein biochemistry, genetics and cell biology will also be used to further understand the role of spectrin and its associated proteins in the regulation of endosomal protein trafficking. Overall the results of this project will generate new paradigms for how spectrins function in the control of cellular growth.
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.
