EFRI-MIKS: Force Sensing and Remodeling by Cell-Cell Junctions in Multicellular Tissues

这项由研究和创新新兴前沿办公室颁发的奖项支持研究细胞之间的机械相互作用的工作，这些相互作用支配着生命的基本过程，并为多细胞生物学中许多悬而未决的问题奠定了基础。机械应力可以调节健康和患病细胞的反应，如更新、生长、细胞死亡或疾病进展。这种机械信号还可以直接调节控制癌症转移、心血管重塑或干细胞分化的信号通路。细胞-细胞黏附结构对外力的机械响应只是最近的文献，但仍然缺乏特征。我们的跨学科团队正在解决生物学中的关键测量挑战，以了解细胞-细胞连接处动态机械载荷的细胞响应。在这个项目中，我们将：1)开发新的工程设备，以成像动态施加载荷下活细胞中的细胞-细胞连接。这些测量将测试多细胞组织型组件中响应外部机械负荷的细胞黏附重塑模型；2)应用创新的单分子分析方法来表征被认为是细胞黏附重塑基础的力依赖型蛋白质-蛋白质相互作用；3)展示一种新型的分子力传感器，它可以直接可视化通过细胞间黏附传递的分子尺度机械力。我们的团队将细胞生物学、结构生物学、工程学和生物物理学方面的专业知识结合在一起，能够很好地解决机械生物学中的基本问题，这些问题是每个单独的研究小组不可能单独解决的。这项工作具有变革数量生物学的潜力，并统一了不断增长的、跨学科的机械生物学领域的独特观点和技能。这项工作的智力价值在于开发了细胞对环境提示做出反应的基本知识和新模型。细胞间和细胞内对机械刺激的反应为表征环境适应和多细胞组装重塑的阈值和机制提供了一个试验台。为我们的实验开发的结果、方法、设备和探针将通过出版物、详细规范和数据库提供给其他研究人员。模型和结果将通过我们的网页、出版物和面向该领域研究人员的研讨会以及公共研讨会论坛进行传播。我们工作的广泛影响在于加强对多细胞机械信号的了解，力学环境在细胞行为中的作用，分子水平上力和位移传感的基本机制，以及在体内和体外研究多细胞系统力学生物学的增强方案、探针和技术的发展。我们的研究主题将被纳入基础工程和生物学课程的教学模块，以及我们实验室内本科生研究经验的发展。PIs积极参与社区外展、本科生研究机会，以及为教师和未被充分代表的学生提供研究经验。这个奖项使我们能够扩大这些努力，让更多的人参与到这项工作中来，并通过社区集市和公开演讲的摊位来展示这项工作。

This award by the Office of Emerging Frontiers in Research and Innovation supports work to study mechanical interactions between cells that govern the basic processes of life and underpin many unresolved questions in multicellular biology. Mechanical stresses can modulate healthy and diseased cell responses such as renewal, growth, cell death or disease progression. Such mechanical signals can also directly regulate signaling pathways controlling cancer metastasis, cardiovascular remodeling or stem cell differentiation. The mechano-response of cell-cell adhesive structures to applied force is only recently documented, yet remains poorly characterized. Our inter-disciplinary team is addressing critical measurement challenges in biology to understand the cellular responses of dynamic mechanical load at cell-cell junctions. In this program, we will: 1) Develop novel engineering devices to image cell-cell junctions in living cells under dynamic applied load. These measurements will test models of cell adhesion remodeling in response to external mechanical load in multicellular tissue-like assemblies; 2) Apply innovative single-molecule assays to characterize force-dependent protein-protein interactions that are hypothesized to underlie cell adhesion remodeling; 3) Demonstrate a new class of molecular force sensors that can directly visualize the transmission of molecular-scale mechanical force through cell-cell adhesions. Our team unites an unusual combination of expertise in cell biology, structural biology, engineering, and biophysics and is well-positioned to tackle fundamental questions in mechanobiology that would be impossible for each individual research group to address alone. This work has transformative potential to revolutionize quantitative biology and unites unique views and skills in the growing, interdisciplinary field of mechanobiology. The intellectual merit of the work lies in the development of basic knowledge and new models for cell response to environmental cues. Inter- and intra-cellular responses to mechanical stimuli offer a test bed for characterizing the thresholds and mechanisms of environmental adaptation and remodeling of multicellular assemblies. The outcomes, methods, devices and probes developed for our experiments will be made available through publications, detailed specifications, and databases for other researchers. Models and results will be disseminated through our webpage, publications and seminars for researchers in the field, and public seminar forums. The broad impact of our work lies in enhancing knowledge of multicellular mechanical signaling, the role of the mechanical environment in cell behaviors, fundamental mechanisms for force and displacement sensing at the molecular scale, and the development of enhanced protocols, probes, and technologies to study the mechanobiology of multicellular systems in vivo and in vitro. Topics of our research will be incorporated in modules for teaching basic Engineering and Biology courses, and the development of undergraduate research experiences within our laboratories. The PIs actively participate in community outreach, undergraduate research opportunities, and research experience for teachers and under-represented student research programs. This award allows us to expand these efforts and include more participation to this work, as well as to showcase the work through public outreach via booths at community fairs and public talks.