Cadherin Adhesion and Mechanosensing

描述(申请人提供)：这项研究扩展了来自这个小组的新的和新的发现，明确地表明钙粘附素复合体是所有粘连组织中必不可少的细胞-细胞黏附蛋白，是张力传感器，探测细胞的机械环境，调节包括形态发生、伤口愈合、组织组织和转移在内的广泛的关键功能。越来越多的证据表明，在发育和成年组织中，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黏附蛋白与细胞骨架网络和细胞核耦合。虽然整合素是公认的力传感器，但我们的新发现表明，钙粘附素也是组织中关键的机械和信号中枢。在这个项目中，我们将推进我们的初步研究，以阐明钙粘附素特定的机械转导途径中的力驱动的分子级联。与竞争技术相比，我们创新的机械测量和动态荧光成像组合具有显著优势，因为它能够对钙粘附素粘连施加直接、可控的局部作用力，同时以高通量格式对机械转导中快速、早期的分子事件进行成像。通过使用强大的生化工具和对内源性收缩力量对细胞-细胞连接的影响的补充研究来加强这一方法论，我们处于战略地位，可以解决关于力通过组织传播的机制的基本的、尚未解决的问题。这项拟议的计划将大大提高我们对组织中机械转导的理解，并为我们开发针对转移或渗漏血管的靶向治疗以及促进组织再生和伤口愈合的长期目标铺平道路。 与公共健康相关：这项拟议的计划扩展了该小组的新发现，表明钙粘附素复合体是所有粘连组织中至关重要的细胞间黏附蛋白，它感知机械力来调节分子和信号级联，控制伤口愈合、形态发生、组织再生和转移等功能。这些研究将在更广泛的机械生物学背景下，在了解力量调节钙粘素依赖功能的机制方面取得重大进展，并为我们开发针对转移、血管泄漏、伤口愈合和组织再生的靶向治疗方法的长期健康相关目标铺平道路。

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. PUBLIC HEALTH RELEVANCE: This proposed program expands on new findings from this group showing that cadherin complexes, which are crucial intercellular adhesion proteins in all cohesive tissues, sense mechanical force to regulate molecular and signaling cascades governing such functions as wound healing, morphogenesis, tissue regeneration, and metastasis. These studies will make major advances in the understanding of mechanisms by which force regulates cadherin-dependent functions, in the broader context of mechano-biology, and pave the way towards our long-term health related goals of developing targeted therapies for metastasis, leaky blood vessels, wound healing, and tissue regeneration.