The objective of this research project is to identify nanoscale mechanisms by which cells sense tension in neighboring cells to regulate critical cell functions. The intellectual merit of this program derives from novel, timely preliminary findings demonstrating definitively i) that an essential class of intercellular adhesion proteins, cadherins, sense force to proportionally alter cell functions and ii) that this function depends on specific binding partners. This research uses an innovative combination of mechanical probes and live cell imaging, to investigate cadherin mechanobiology, and constitutes an entirely new research area. This program is innovative because intercellular mechanosensing and its impact on the broader cell mechanics is an almost entirely unexplored research area.
This work will have broad impact because cadherins are critical for development, organized tissue remodeling, and regulating tissue barriers. Cadherins capacity to sense force would dramatically impact how they regulate cell functions, and expand the broad impact of mechanical force on cell-cell communication. Because of cadherins importance for human health and general biology, this work will impact fields ranging from basic biology to bioengineering and the clinic. The educational impact of this program includes outreach to women and minorities at pre-college and undergraduate levels through the Girls Adventures in Mathematics and Engineering (GAMES)program and with the Summer Research Opportunity Program for minorities (SROP) at the University of Illinois. We will implement technologies in this proposal in GAMES workshops and research activities for students in the SROP program. This grant will enable us to continue mentoring students in these outreach programs.
Outcomes of this research include the identification of a fundamental mechanism of mechanotransduction in living cells, and the demonstration that the force-activated biochemical signals not only alter the perturbed cell, but also mechanically integrate several cells within the tissue. Under Specific Aim 1, we investigated the mechanism underlying a recent discovery by us that protein complexes at the adhesive contacts between cells in tissues transduce mechanical forces to activate signaling cascades in the cell. We focused on proteins called cadherins, which are the molecular Velcro that holds cells together in tissues. The intellectual merit of this investigation is that our findings demonstrated that these protein complexes do more than just hold cells together—they also convert mechanical stimuli into biochemical signals that alter cell mechanics as well as the mechanical properties of the tissue. Our findings under Specific Aim 2 then uncovered fundamental molecular biochemical signaling events activated during force transduction in the cell, and we demonstrated initial impact of these signals on cell mechanics. We then uncovered the basic events in the mechanotransduction process in living cells, and we identified molecular design rules of the nanomachine that is responsible for the mechanotransduction event. More broadly, under Specific Aim 3, we demonstrated that mechanotransduction depends on the specific type of ligand that binds to cadherins on the cell, and this differential mechanical response could influence how cells organize relative to each other in developing tissues. Finally, under Specific Aims 2 and 3, we demonstrated that cadherin-mediated mechanotransduction signals not only integrate other adhesion proteins in the cell, but also propagate signals to adjacent cells to globally alter tissue mechanics. The intellectual merit of this work is the demonstration that cadherin complexes are central mechanical and signaling hubs both within the cell in a broader force sensitive network in tissues. Because of the importance of mechanics in a wide range of biological processes in development, disease, tissue regeneration, wound healing and others, these findings will have broad impact in several different areas of biology and bioengineering. Broader impacts of this work also include several outreach activities involving the local high schools and middle school girls. We participated in a weeklong summer camp Girls Adventures in Mathematics Engineering and Science (GAMES) managed by the College of Engineering. We organized hands on teaching activities that expose girls to bioengineering principles and career opportunities. We also participate in a day camp "Bonding with Chemistry" organized by the Department of Chemistry. Students supported on this grant also participated in numerous outreach activities to local high schools.
