Mechanotransduction from Cells to Tissues: Mechanisms and Physiological Significance

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Mechanical cues are essential for life. They determine how tissues organize in embryos, and they guide tissue regeneration and even plant growth. Cells use proteins to connect to each other, and also to sense the forces between them. Discovering how the cells convert forces on the connecting proteins into chemical signals is the goal of this research. The importance of this work is to build an understanding of how mechanical inputs at the cell level control the tissue physiology, shape, size and strength. At the cell level, the research will establish how the networks of adhesion proteins that connect between the cells modify the mechanical properties of the cells. The next question to answer is how the cell level changes mechanically change the tissue level mechanical properties. As part of this project, the research investigators will work with local high school and middle school girls and underrepresented minorities to teach how science can be an interesting career.The broad goals of this program are to establish how mechano-sensitive adhesion proteins integrate mechanical cues to regulate cell mechanics, the propagation of mechanical information through tissues, and the regulation of tissue functions. Under Aim 1, combined magnetic twisting cytometry and traction force microscopy will enable us to identify biochemical and mechanical mechanisms integrating E-cadherin force transduction signaling to integrin activation at the basal plane and increased cell contractility. Aim 2 of this proposal uses biochemical perturbations and dynamic fluorescence imaging, in conjunction with mechanical perturbations, to establish mechanisms by which force transduction signals are propagated across cell boundaries to the surrounding tissue. In Aim 3, we then demonstrate the physiological consequences of altered tissue mechanics on the permeability of epithelial tissues. The latter studies will investigate the impact on hydraulic pressure and tissue mechanics on the regulation of macromolecules flux across epithelial tissue. The intellectual significance of this work will be the identification of multiscale, mechano-transduction mechanisms that are essential for establishing comprehensive, predictive models of mechanobiology.