Collaborative Research: Understanding the Fractal Physics of the Cell Cortex

该项目将研究活细胞与其物理环境相互作用方式的基本方面。众所周知，细胞对输入（如外力和它们所生存的组织的刚度）表现出广泛的机械响应，但试图描述细胞复杂机械特性的模型是不完整的，并且无法预测细胞行为的关键方面。 提高对细胞机械行为的物理理解是重要的，因为这种活动既驱动正常的生物过程，如胚胎的发育，也驱动病理过程，包括癌症的扩散。这个项目是约翰霍普金斯大学和宾夕法尼亚大学的研究人员之间的合作。它将建立在研究人员最近的一项发现的基础上，该发现通过利用细胞物理学和一类称为软玻璃的材料的动力学之间的类比，有望对细胞力学有新的理解。 这些材料表现出间歇性运动，以响应外部应力，在很宽的长度和时间尺度范围内，以一种让人想起地震或雪崩的方式。该研究小组最近使用一种新方法在细胞中观察到了这种现象，该方法可以测量细胞的内在机械特性以及它们以前所未有的准确度对环境施加的高度动态和波动力。在该项目中，使用该工具的新实验将用于指导细胞力学关键方面的新物理模型的开发。然后，该模型将用于推进对细胞对关键线索的物理反应起源的理解，例如环境的硬度。 该项目的一个重要成果是为参与者提供跨学科研究培训，包括博士后研究员，研究生，硕士生和本科生，这将为他们在学术界和工业界的职业生涯做好准备。该项目还将通过在约翰霍普金斯大学的研究实习为巴尔的摩市的高中学生提供教育机会，并将为K-12使用和由宾夕法尼亚大学赞助的费城科学推广活动开发交互式教学材料。这个项目将开发一个长期存在的肌动球蛋白皮质和软玻璃质材料（SGMs）之间的类比。 Co-PI Crocker最近开发了第一个成功的模型，从第一原理解释了SGM的不寻常机制。该团队使用Co-PI赖希最近开发的主动微柱阵列探测器进行的初步实验为研究主动细胞骨架动力学提供了一个独特的强大实验平台，表明皮质力学和波动与SGM模型中的非常相似。 该项目的目标是（i）对细胞皮层的力学和微观波动进行详细的实验研究;（ii）使用这些数据来开发、改进和验证一个新的涌现皮层力学的机械模型，该模型将最近的见解从SGMs带到皮层;以及（iii）在细胞将其内部硬度与其周围环境相匹配的能力的背景下，使用该模型来理解细胞机械“由外向内”信号传导。这将使测试一个新的假设：像SGMs，皮质活性物质的行为是系统的高维能量景观的结果，产生分形能量最小化路径，并在这个分形能量景观的机械平衡的演变导致细胞的涌现动力学和流变学。通过将亚细胞皮层动力学的描述超越现象学，并在肌动球蛋白的纳米级分子生物物理学和细胞水平力学之间提供桥梁，这项工作将有助于进一步了解更复杂的细胞，该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的知识产权进行评估来支持。优点和更广泛的影响审查标准。

This project will investigate fundamental aspects of the ways that living cells interact with their physical environment. It is known that cells exhibit a wide range of mechanical responses to inputs such as external forces and the stiffness of the tissues in which they live, but models that attempt to describe the complex mechanical properties of cells are incomplete and cannot predict key aspects of cellular behavior. Improved physical understanding of cellular mechanical behavior is important as such activity drives both normal biological process, such as the development of embryos, as well as pathological ones including the spread of cancer. This project is a collaboration between researchers at Johns Hopkins University and the University of Pennsylvania. It will build on a recent discovery by the Investigators that promises new understanding of cell mechanics by exploiting analogies between the physics of cells and the dynamics of a class of materials termed soft glasses. These materials exhibit intermittent motion in response to external stresses, over a wide range of length and time scales, in a manner that is reminiscent of earthquakes or avalanches. The research team recently observed such phenomena in cells using a novel approach that can measure both cells’ intrinsic mechanical properties and the highly dynamic and fluctuating forces they exert on their environment with unprecedented accuracy. In this project, new experiments with this tool will be used to guide the development of a new physical model of key aspects of cellular mechanics. This model will then be used to advance understanding of the origin of cells’ physical responses to critical cues, such as the stiffness of their environment. An important outcome of this project will be the interdisciplinary research training it will provide for its participants, including a postdoctoral fellow, graduate students, Masters students and undergraduates, that will prepare them for careers in academia and industry. The project will also provide educational opportunities for Baltimore City high school students through research internships at Johns Hopkins University, and interactive instructional materials will be developed for K-12 use and for science outreach initiatives in Philadelphia sponsored by the University of Pennsylvania.The actomyosin cortex and associated machinery of living cells is a remarkable example of a self-assembled active material. This project will develop a long-standing analogy between the actomyosin cortex and soft-glassy materials (SGMs). Co-PI Crocker has recently developed the first successful model to explain the unusual mechanics of SGMs from first principles. Initial experiments by the team, using active micropost array detectors recently developed by Co-PI Reich, which provide a uniquely powerful experimental platform for studying active cytoskeletal dynamics, suggest that cortical mechanics and fluctuations closely resemble those in the SGM model. The goals of this project are (i) to make a detailed experimental study of the mechanics and microscopic fluctuations of the cell cortex; (ii) to use that data to develop, refine and validate a new mechanistic model of emergent cortical mechanics that carries over the recent insights from SGMs to the cortex; and (iii) to use this model to understand cellular mechanical “outside-in” signaling in the context of cells’ ability to match their internal stiffness to that of their surroundings. This will enable testing a novel hypothesis: that like SGMs, cortical active matter behavior is the consequence of the system’s high-dimensional energy landscape giving rise to fractal energy minimizing paths, and that the evolution toward mechanical equilibrium in this fractal energy landscape leads to cells’ emergent dynamics and rheology. By moving the description of subcellular cortical dynamics beyond the phenomenological and providing a bridge between the well understood nanoscale molecular biophysics of actomyosin and cell-level mechanics, this work will help enable further understanding of more complex cell-level functions such as motility and tissue morphogenesis.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.