Collaborative Research: Understanding the Fractal Physics of the Cell Cortex

这个项目将研究活细胞与其物理环境相互作用的基本方面。众所周知，细胞对外力和其所在组织的硬度等输入表现出广泛的机械响应，但试图描述细胞复杂力学特性的模型是不完整的，无法预测细胞行为的关键方面。改善对细胞力学行为的物理理解是重要的，因为这种活动既推动了正常的生物过程，如胚胎的发育，也推动了包括癌症扩散在内的病理过程。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合作完成的。它将建立在研究人员最近的一项发现的基础上，通过利用细胞物理学和一种名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。这些材料在大范围的长度和时间尺度上表现出响应外部应力的间歇性运动，其方式使人联想到地震或雪崩。研究小组最近使用一种新的方法在细胞中观察到了这种现象，这种方法可以前所未有的准确地测量细胞的内在机械属性以及它们对环境施加的高度动态和波动的力。在这个项目中，将使用这个工具进行新的实验，以指导细胞力学关键方面的新物理模型的开发。然后，这个模型将被用来促进对细胞对关键提示的物理反应的起源的理解，例如环境的僵硬。该项目的一个重要成果将是为参与者提供跨学科的研究培训，包括博士后、研究生、硕士和本科生，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生提供教育机会，并将开发互动教学材料，供K-12使用，并由宾夕法尼亚大学赞助用于费城的科学推广活动。肌动球蛋白皮质和相关的活细胞机械是自组装活性材料的一个显著例子。该项目将开发肌动球蛋白皮质和软玻璃材料(SGM)之间的长期类比。科罗克最近开发了第一个成功的模型，从第一性原理解释了SGM的不寻常机制。该团队使用Co-Pi Reich最近开发的有源微柱阵列探测器进行的初步实验表明，皮质力学和涨落非常类似于SGM模型中的那些。有源微柱阵列探测器为研究活跃的细胞骨架动力学提供了独特而强大的实验平台。这个项目的目标是(I)对细胞皮质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紧急皮质力学机制模型，该模型继承了从SGM到皮质的最新见解；以及(Iii)使用该模型在细胞匹配其内部刚性与其周围环境的能力的背景下理解细胞机械“由外而内”的信号。这将使一种新的假设得以检验：与SGM一样，皮质活动物质的行为是系统高维能量格局的结果，导致了分形能量最小化路径，并且在这种分形能量格局中朝着力学平衡的演化导致了细胞的涌现动力学和流变学。通过将对亚细胞皮质动力学的描述超越现象学，并在众所周知的肌动球蛋白纳米级分子生物物理学和细胞水平力学之间架起一座桥梁，这项工作将有助于进一步理解更复杂的细胞水平功能，如运动性和组织形态发生。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.