Mechanotransduction from Cells to Tissues: Mechanisms and Physiological Significance

机械提示对生命至关重要。它们决定组织如何在胚胎中组织，并指导组织再生甚至植物生长。 细胞利用蛋白质相互连接，并感知它们之间的力。 发现细胞如何将连接蛋白质的力转化为化学信号是这项研究的目标。这项工作的重要性是建立在细胞水平的机械输入如何控制组织的生理，形状，大小和强度的理解。 在细胞水平上，研究将确定细胞之间连接的粘附蛋白网络如何改变细胞的机械特性。下一个要回答的问题是细胞水平的变化如何机械地改变组织水平的机械特性。 作为该项目的一部分，研究人员将与当地高中和初中女生以及代表性不足的少数民族合作，教授科学如何成为一个有趣的职业。该项目的主要目标是建立机械敏感粘附蛋白如何整合机械线索来调节细胞力学，机械信息通过组织的传播，以及组织功能的调节。在目标1下，结合磁扭转细胞术和牵引力显微镜将使我们能够确定整合E-钙粘蛋白力转导信号传导到基底面整联蛋白激活和增加细胞收缩性的生化和机械机制。 该提案的目的2使用生物化学扰动和动态荧光成像，结合机械扰动，以建立力转导信号跨细胞边界传播到周围组织的机制。 在目标3中，我们展示了改变组织力学对上皮组织渗透性的生理后果。后面的研究将调查液压和组织力学对调节跨上皮组织的大分子通量的影响。 这项工作的智力意义将是识别多尺度，机械转导机制，建立全面的，预测模型的机械生物学是必不可少的。

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.