Mechanotransduction from Cells to Tissues: Mechanisms and Physiological Significance

机械线索对生命至关重要。它们决定了组织在胚胎中如何组织，它们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量。发现细胞如何将作用在连接蛋白上的力转化为化学信号是本研究的目标。这项工作的重要性在于建立对细胞水平上的机械输入如何控制组织生理学、形状、大小和强度的理解。在细胞水平上，该研究将确定连接细胞之间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机械变化如何改变组织水平的机械特性。作为该项目的一部分，研究人员将与当地的高中和初中女生以及未被充分代表的少数民族合作，教授科学如何成为一项有趣的职业。该计划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，机械信息在组织中的传播，以及组织功能的调节。在Aim 1下，结合磁扭转细胞术和牵引力显微镜将使我们能够识别将E-cadherin力转导信号整合到基面整合素激活和细胞收缩性增加的生化和机械机制。本提案的目标2使用生化扰动和动态荧光成像，结合机械扰动，建立力转导信号跨越细胞边界传播到周围组织的机制。在Aim 3中，我们随后展示了改变的组织力学对上皮组织渗透性的生理后果。后一项研究将探讨液压和组织力学对上皮组织中大分子通量调节的影响。这项工作的智力意义在于确定多尺度的机械转导机制，这对于建立机械生物学的综合预测模型至关重要。

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.