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

EFRI-MIKS：多细胞组织中细胞-细胞连接的力传感和重塑

• 批准号: 1136790
• 负责人: Beth Pruitt
• 金额: $ 200万
• 依托单位: Stanford University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1136790&HistoricalAwards=false
• 关键词: EFRI; MIKS; Force; Sensing; Remodeling

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.

新兴领域的研究和创新办公室的奖项支持研究控制生命基本过程的细胞之间的机械相互作用，并为多细胞生物学中的许多未解决的问题支撑。机械应力可以调节健康和患病的细胞反应，例如更新，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。细胞细胞粘附结构对应用力的机械反应直到最近才记录在案，但仍未表征。我们的跨学科团队正在应对生物学的关键测量挑战，以了解细胞 - 细胞连接处动态机械负荷的细胞反应。在此程序中，我们将：1）开发新型的工程设备，以在动态施加的载荷下在活细胞中图像细胞电池连接。这些测量值将测试细胞粘附重塑的模型，以响应多细胞组织样组件中的外部机械负荷； 2）应用创新的单分子测定法来表征力依赖性蛋白 - 蛋白质相互作用，这些蛋白质蛋白质相互作用被认为是细胞粘附重塑的基础； 3）展示了一类新的分子力传感器，该传感器可以直接可视化分子尺度机械力通过细胞细胞粘附的传播。我们的团队结合了细胞生物学，结构生物学，工程和生物物理学方面的专业知识的异常组合，并且有很好的位置以解决机械生物学中的基本问题，而每个研究小组都无法单独解决。这项工作具有彻底改变定量生物学的变革潜力，并在不断发展的机械生物学跨学科领域中统一了独特的观点和技能。这项工作的智力优点在于发展基础知识和新模型，以响应环境线索。对机械刺激的细胞间和细胞内反应提供了一个测试床，以表征多细胞组件的环境适应和重塑的阈值和机制。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，可为其他研究人员提供。模型和结果将通过我们的网页，出版物和研讨会以及该领域的研究人员以及公共研讨会论坛传播。我们工作的广泛影响在于增强对多细胞机械信号传导的了解，机械环境在细胞行为中的作用，在分子尺度上的力和位移传感的基本机制，以及增强的方案，探针和技术的发展，以研究研究多细胞系统的机械生物学in Vivo的机械生物学。我们的研究主题将纳入教授基础工程和生物学课程的模块中，以及我们实验室内的本科研究经验的发展。 PI积极参与社区外展，本科研究机会以及为教师和代表性不足的学生研究计划的研究经验。该奖项使我们能够扩大这些努力，并包括更多参与这项工作，并通过社区博览会和公众谈判通过公共展览来展示这项工作。