Cadherin Adhesion and Mechanosensing

描述（由申请人提供）：本研究扩展了该组的新发现，这些发现明确表明钙粘蛋白复合物（所有粘性组织中的必需细胞-细胞粘附蛋白）是张力传感器，可探测细胞的机械环境，以调节广泛的关键功能，包括形态发生、伤口愈合、组织组织化和转移。越来越多的证据表明，在发育和成人组织中，关键的生物学功能受到机械环境的调节，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枢纽。 在这个项目中，我们推进我们的初步调查，以阐明力驱动的，分子级联的钙粘蛋白特异性mechanotransductionpathway。我们的机械测量和动态荧光成像的创新组合相比竞争技术具有显著优势，因为它能够将直接，受控的局部力应用于钙粘蛋白粘附，同时以高通量格式成像机械转导中的快速，早期分子事件。通过增强这种方法与强大的生化工具和补充研究的内源性收缩力对细胞-细胞连接的影响，我们的战略定位，以解决基本的，未解决的问题，通过组织的力传播的机制。这项计划将大大推进我们对组织中机械转导的理解，并为我们开发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.