NanoMedicine Center for Mechanical Biology (RMI)

说明(应用程序摘要) 纳米技术承诺提供必要的工具来解决一个主要的悬而未决的问题：如何整合细胞组件以同步工作？尽管在细胞过程的化学集成方面已经投入了大量的工作，但我们认为机械因素也同样重要。细胞对机械信号、机械转导的反应决定了生物体的形状，对许多功能至关重要。机械转导的缺陷是许多疾病的基础，如癌症、免疫紊乱、遗传畸形和神经病。为了了解力、刚性和形状在调节细胞功能中的作用，需要在单分子水平和系统水平上开发这种机制的详细量化图，描述单分子如何对机械力做出反应。此外，我们还需要了解外力是如何调控信号通路和基因表达的。纳米技术和现代细胞生物学的工具现在提供了在微米和纳米尺度上研究这些复杂过程的许多物理方面的手段。我们认为，以定量的方式理解机械转导的最好方法是开发一种从单个分子到整个系统的综合方法。我们的团队拥有广泛的专业知识，包括细胞生物物理学和纳米制造、高级荧光显微镜和图像分析、免疫学和辅助双层制造、发育生物学和信号系统建模。所有小组都有多个项目正在进行中，以解决机械转导中的重要问题。我们的初步结果表明，许多不同的细胞能够利用类似的力感知、力生成和力承载系统，这促使我们认为，对于许多任务，细胞可以使用共同的工具集，而表型差异是由于使用一种工具的程度和位置与另一种工具的不同造成的。这个由科学家、工程师和数学家组成的多元化团队拥有在细胞和分子水平上开发和测试机械转导模型的专业知识和能力。我们团队开发的纳米技术使我们能够快速筛选得出给定功能所需的最佳基质刚性、形状和间距。我们的计划是定制这些技术，以测试细胞过程的重要生物和工程模型。我们正在单细胞水平上，在细胞间相互作用的水平上，重点放在免疫突触上，以及在触觉发育的多细胞水平上解决这些问题。通过了解细胞中机械转导的分子机制，我们可以开发出在细胞-细胞和多细胞系统中进行测试的模型。这项研究将提供重要的新方法来阻止转移，促进伤口愈合和许多其他依赖于机械转导的医学问题。

DESCRIPTION (application abstract) Nanotechnology promises to deliver the needed tools to address one of the major unsolved questions: How are cell components integrated to work in synchrony? Although much work has been put into the chemical integration of cellular process, we believe that mechanical factors are equally important. Cellular responses to mechanical cues, mechanotransduction, determine the shape of the organism and are critical for many functions. Defects in mechanotransduction underlie many diseases such as cancers, immune disorders, genetic malformations, and neuropathies. To understand the roles of force, rigidity and form in regulating cell functions requires the development of detailed quantitative pictures of this machinery at both the single molecule level, describing how single molecules respond to mechanical forces, and at the systems level. Further, we will need an understanding of how forces regulate signaling pathways and gene expression. The tools of nanotechnology and modern cell biology now provide the means to investigate many of the physical aspects of these complex processes at the micro- and nano-meter scale. We feel that the best way to understand mechanotransduction in a quantitative way is to develop an integrated approach, ranging from individual molecules to whole systems. Our team has a wide range of expertise including Cell Biophysics and Nanofabrication, Advanced Fluorescence Microscopy and Image Analysis, Immunology and Supported Bilayer Fabrication, Developmental Biology and Signaling Systems Modeling. All groups have multiple projects underway to address important questions in mechanotransduction. Our preliminary results indicate that many different cells are capable of utilizing similar force-sensing, force-generating and force-bearing systems, which stimulates us to think that for many tasks, cells can use a common tool set and phenotypic differences result from differences in the extent and location of use of one tool versus another. This diverse team of scientists, engineers and mathematicians has the expertise and the capabilities to develop and test models of mechanotransduction at the cell and molecular level. Nanotechnology developed in our group enables us to rapidly screen for the optimal matrix rigidity, form, and spacing needed to elicit a given function. Our plan is to customize these technologies to test important biological and engineering models of cell processes. We are addressing these questions at the single cell level, at the level of cell-cell interactions with a focus on the immune synapse, and at the multicellular level in the development of touch sensation. From an understanding of the molecular mechanisms of mechanotransduction in cells, we can develop models to be tested in the cell-cell and multicellular systems. This research will provide important new approaches to stop metastases, to facilitate wound healing and many other medical problems that depend upon mechanotransduction.