Cadherin Adhesion and Mechanosensing

描述（由申请人提供）：本研究扩展了本小组的新发现，明确地表明钙粘蛋白复合物是所有黏附组织中必需的细胞-细胞黏附蛋白，是张力传感器，探测细胞的机械环境，调节广泛的关键功能，包括形态发生，伤口愈合，组织组织和转移。越来越多的证据表明，在发育和成人组织中，关键的生物学功能是由机械环境调节的，机械环境通过细胞表面粘附蛋白与细胞骨架网络和细胞核偶联。虽然整合素是公认的力传感器，但我们的新发现表明，钙粘蛋白也是组织中关键的机械和信号中枢。在这个项目中，我们推进了我们的初步研究，以阐明钙粘蛋白特异性机械转导途径中力驱动的分子级联。我们创新的机械测量和动态荧光成像的结合比竞争技术有很大的优势，因为它可以应用直接的、可控的局部力来粘附钙粘蛋白，同时以高通量的形式对机械转导中的快速、早期分子事件进行成像。通过强大的生化工具和对内源性收缩力对细胞-细胞连接影响的补充研究来增强这种方法，我们在战略上定位于解决关于力在组织中传播机制的基本的、未解决的问题。该计划将大大促进我们对组织机械转导的理解，并为我们开发针对转移或渗漏血管的靶向治疗以及增强组织再生和伤口愈合的长期目标铺平道路。

DESCRIPTION (provided by applicant): This research expands on new and novel findings from this group that show definitively that cadherin complexes, essential cell-cell adhesion proteins in all cohesive tissues, are tension sensors that probe the mechanical environment of the cell to regulate a wide range of critical functions including morphogenesis, wound healing, tissue organization, and metastasis. Increasing evidence shows that crucial biological functions, in development and in adult tissues, are regulated by the mechanical environment, which couples to the cytoskeletal network and nucleus via cell surface adhesion proteins. Although integrins are well-established force sensors, our new findings show that cadherins are also critical mechanical and signaling hubs in tissues. In this program, we advance our initial investigations to elucidate the force-actuated, molecular cascades in the cadherin-specific mechanotransduction pathway. Our innovative combination of mechanical measurements and dynamic fluorescence imaging has substantial advantages over competing technologies because it enables the application of direct, controlled localized force to cadherin adhesions, while simultaneously imaging the rapid, early molecular events in mechanotransduction, in a high throughput format. By enhancing this methodology with powerful biochemical tools and complementary studies of the impact of endogenous contractile force on cell-cell junctions, we are strategically positioned to address fundamental, unresolved questions regarding mechanisms of force propagation through tissues. This proposed program will significantly advance our understanding of mechano-transduction in tissues, and pave the way towards our long-term goals of developing targeted therapies for metastasis or leaky blood vessels, and of enhancing tissue regeneration and wound healing.