Mechanism of alpha catenin tension sensing

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1132116LeckbandIntellectual merit. This program extends recent innovative findings by this team demonstrating that cadherin complexes--critical proteins at cell-to-cell junctions in all soft tissues--sense the mechanical properties of the cell environment and proportionally regulates cell functions. A major objective is to use sensitive force probes to test proposed mechanisms of mechano-sensing at cadherin junctions. A new innovation will be the development of a fluorescence-based intracellular biosensor to directly test whether mechanical force induces conformational changes in a putative force sensor at intercellular adhesions. This sensor will enable direct visualization of dynamic, force-actuated changes at cadherin-based adhesions in live cells. This will transform the ability to investigate mechanotransduction at intercellular junctions, and enable the real-time visualization of spatial maps of mechanotransduction, in a living cell. This multidisciplinary research involves sensitive mechanical measurements, probe development, and dynamic, subcellular imaging of live cells. This program is innovative because cadherin-based, intercellular mechanosensing and its impact on broader cell mechanics is an almost entirely unexplored research area.This research will have broad impact because cadherins are critical for tissue genesis, organized tissue remodeling, and regulating tissue barriers. Cadherins' capacity to sense force would dramatically impact how they regulate cell functions, and expand the impact of mechanical force on cell-cell communication. Because cadherins are important for human health and tissue biology, this work will impact fields ranging from developmental biology to bioengineering and the clinic. The educational impact lies in the 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. This grant will enable the implementation of technologies described in this proposal in GAMES workshops and in SROP research projects, and the continued mentoring women and underrepresented minorities.