Collaborative Research: Experimentally guided mathematics for the mechanochemistry of cell shape dynamics

在细胞生物学中提出了一种综合的数学-实验努力，重点是运动细胞表型的形态和动力学。具体地说，我们探索和模拟了化学-机械转导的分子机制，以及机械对化学动力学的反馈，以及活细胞的空间和时间分辨率。建模的目标是一个整合详细生物学数据和测试生物物理假设的平台，以及一个针对特定细胞外环境中的细胞的预测性模拟工具。该模型平台结合了细胞亚结构鉴定和性质表征(双层膜、皮质层、胞浆和细胞核)的进展，以及特定信号分子、它们的动力学以及它们在机械激活和失活中的作用(Rho GTP酶家族)的进展。实验挑战集中于在活细胞中实现时空分辨率，以便可以测量机械-化学反馈机制，并与模型模拟进行比较。数学上的挑战在于对每个细胞亚结构及其自由边界的真实非平衡描述和模拟，对变形亚结构中信号分子物种的反应和扩散，以及通过机械力化学转导的时空激活。雅各布森实验室确定的一种特殊的细胞运动表型是这一努力的试验台，它可以维持微管的形态振荡。这一努力的一个影响是提供了一个有效的平台来模拟活细胞的形态动力学，并结合实验方案来扰乱细胞内的化学或机械过程。细胞的振荡表型是一个模型系统，在这个模型系统中，化学诱导的机械扰动(微管的破坏)导致强大的、放大的反应，这为机械力化学转导机制提供了假设检验。该模型和实验方法将为其他细胞运动表型及其潜在的生化和力学基础提供探索工具，包括与起泡和分裂相关的戏剧性拓扑变化。动态细胞结构模拟工具将在高性能计算环境中实现，以解决非平衡、异质细胞的复杂性。另一个影响在于培训了一批新的数学家和生物学家，他们相互学习，了解生物学原理和实验方法，以及建模、模拟和实验验证的数学。这项研究的结果将提高对包括癌症在内的许多由于细胞骨架失调而引起的疾病的机制的理解。

An integrated mathematical-experimental effort in cell biology is proposed, focusing on morphology and dynamics of motile cell phenotypes. Specifically, we probe and model the molecular mechanisms of chemical-mechanical transduction, and mechanical feedback to chemical kinetics, with intracellular spatial and temporal resolution of a living cell. The modeling goal is a platform to integrate detailed biological data and test biophysical hypotheses, with a predictive simulation tool for a cell in a specified extracellular environment. The model platform incorporates advances in cell substructure identification and property characterization (bilayer membrane, cortical layer, cytosol and nucleus), coupled with advances in specific signaling molecules, their kinetics, and their role in mechanical activation and deactivation (Rho family of GTPases). The experimental challenges concentrate on achieving spatio-temporal resolution in living cells, so that mechanical-chemical feedback mechanisms can be measured and compared with model simulations. The mathematical challenges lie in a faithful non-equilibrium description and simulation of each cell substructure and its free boundaries, of reacting and diffusing signaling molecular species in deforming substructures, and of the spatio-temporal activation via mechanochemical transduction. A specific cell motility phenotype identified by the Jacobson lab that sustains morphological oscillations with disruption of microtubules is the test-bed for this effort.One impact of this effort is an available platform to simulate living cell morphological dynamics in conjunction with experimental protocols to perturb intracellular chemical or mechanical processes. The oscillation phenotype of the cell is a model system whereby a chemically induced mechanical perturbation (disruption of microtubules) leads to a robust, amplified response that affords hypothesis testing for mechanochemical transduction mechanisms. The model and experimental methods will provide exploratory tools for other cell motility phenotypes and their underlying biochemical and mechanical basis, including dramatic topological changes associated with blebbing and division. The dynamical cell structure simulation tool will be implemented in a high performance computing environment to resolve the complexity of the non-equilibrium, heterogeneous cell. Another impact lies in the training of a new cohort of mathematicians and biologists who learn with and from one another and understand biological principles and experimental methods and the mathematics of modeling, simulation and experimental validation. The outcome of this research will improve the mechanistic understanding of many disorders due to a dysregulation of the cytoskeleton, including cancers.