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

一个综合的药理学实验的努力，在细胞生物学的建议，侧重于运动细胞表型的形态和动力学。 具体来说，我们探测和建模的化学机械转导的分子机制，和机械反馈化学动力学，与活细胞的细胞内空间和时间分辨率。 建模的目标是一个平台，以整合详细的生物数据和测试生物物理假设，与预测模拟工具的细胞在一个指定的细胞外环境。 该模型平台结合了细胞亚结构鉴定和特性表征（双层膜，皮质层，胞质溶胶和细胞核）的进展，以及特定信号分子，其动力学及其在机械活化和失活中的作用（Rho家族的GTP酶）的进展。 实验的挑战集中在实现活细胞的时空分辨率，使机械化学反馈机制可以测量和模型模拟比较。 数学上的挑战在于一个忠实的非平衡描述和模拟每个细胞的子结构和它的自由边界，反应和扩散的信号分子物种在变形的子结构，和时空激活通过机械化学转导。雅各布森实验室鉴定的一种特定的细胞运动表型，通过破坏微管来维持形态振荡，这是这项工作的试验平台。这项工作的一个影响是一个可用的平台，可以模拟活细胞形态动力学，并结合实验方案来扰动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，其中化学诱导的机械扰动（微管的破坏）导致一个强大的，放大的反应，提供假设检验的机械化学转导机制。 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机械基础提供探索工具，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，异构细胞的复杂性。另一个影响在于培养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许多由于细胞骨架失调而引起的疾病（包括癌症）的机械理解。

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.