Models and computation of intracellular signaling in single and collective cell migration

单细胞和集体细胞迁移中细胞内信号传导的模型和计算

• 批准号: RGPIN-2020-04067
• 负责人: EdelsteinKeshet, Leah
• 金额: $ 5.87万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=758506
• 关键词: Models; computation; intracellular; signaling; single

Many cells respond to stimuli by directed motility. For example, white blood cells (neutrophils) polarize and move persistently towards chemical signals. Cell motility entails dynamic changes in structural proteins of the cytoskeleton (primarily filamentous actin, F-actin). This, in turn, is regulated by proteins that promote assembly and disassembly of the actin network or activity of molecular motors (myosin) that pull on it and reshape it. At the core of the cell-migration regulatory cascades are a family of proteins known as Rho GTPases (e.g. Rac, Rho, Cdc42) to which stimuli from receptors, upstream effectors, and feedback from downstream are funneled. GTPases are activated by GEFs, inactivated by GAPS, and "wired together" by mutual crosstalk. Using mathematical modeling, I propose to investigate how the dynamics of GTPases impacts and scale across three levels of biological organization: subcellular structures (cell edge protrusion, wound repair), cell-cell and cell-matrix interactions, and multicellular tissue dynamics. My methods include ordinary and partial differential equation (ODE, PDE) models to describe spatiotemporal GTPase distributions and cell behaviour. Using nonlinear dynamics, bifurcations, approximation methods and simulations, I characterize solutions and predict how behaviour depends on biologically tunable parameters. I also use abstract theory of reaction-diffusion equations (RDEs) to identify possible behaviour. Scaling up to multiple cells, I adapt the mathematics of "swarms" to the microworld of collective cell dynamics. Cell-cell interaction via adhesion, mechanical or chemical signaling, long filopodia, etc., can be depicted (by integro-PDEs with nonlocal "kernels"). My innovation is to include GTPase activity which affects cell spreading/contractility, and hence the range and strength of interactions (kernel magnitudes, ranges). The analysis is complemented with simulations in one and two spatial dimensions (1D, 2D), that can be directly compared to experimental data from collaborators. My ongoing and new collaborations span the subcellular to tissue scales: (1) With W Bement (Wisconsin, cell wound repair) (2) With JinSeok Park (Yale and USC) and Andre Levchenko (Yale), on cell-ECM interactions and (3) With Cal Roskelley (UBC) and Arnold Hayer (McGill) on cell-cell collisions in vitro; with Paul Kulesa (Stowers, neural crest cells) and with Joy Richman (UBC) on collective cell migration and morphogenesis. Training HQP in interdisciplinary research will take place at all levels, from undergraduates, through graduate students and post-docs, with strong EDI components. My key aims are to link subcellular signaling to the behaviour of single cells, cell groups, and tissues on one hand, and to bridge between abstract mathematics and specific applications on the other hand.

许多细胞通过定向运动对刺激作出反应。例如，白细胞(中性粒细胞)极化并持续向化学信号移动。细胞运动需要细胞骨架结构蛋白的动态变化(主要是丝状肌动蛋白，F-肌动蛋白)。反过来，这又受到促进肌动蛋白网络组装和拆解的蛋白质或拉动和重塑肌球蛋白的分子马达(肌球蛋白)的活动的调节。细胞迁移调控级联反应的核心是一系列被称为Rho GTP酶的蛋白质(例如Rac、Rho、CDC42)，来自受体、上游效应器和下游反馈的刺激被输送到该家族。GTP酶由GEF激活，由间隙失活，并通过相互串扰“连接在一起”。利用数学模型，我建议研究GTP酶的动力学如何影响和扩展三个层次的生物组织：亚细胞结构(细胞边缘突起、伤口修复)、细胞-细胞和细胞-基质相互作用，以及多细胞组织动力学。我的方法包括描述GTPase时空分布和细胞行为的常微分方程和偏微分方程(ODE，PDE)模型。利用非线性动力学、分叉、近似方法和模拟，我描述了解的特征，并预测了行为如何依赖于生物可调参数。我还使用反应扩散方程(RDES)的抽象理论来识别可能的行为。扩大到多个细胞，我使“蜂群”的数学适用于集体细胞动力学的微观世界。通过黏附、机械或化学信号、长丝足等的细胞-细胞相互作用可以被描述(通过带有非局部“核”的整合型PDE)。我的创新是包括影响细胞伸展/收缩的GTPase活性，从而影响相互作用的范围和强度(核数量级，范围)。分析的补充是一维和二维(一维、二维)的模拟，可以直接与合作者的实验数据进行比较。我正在进行的新的合作跨越亚细胞到组织尺度：(1)与W Bement(威斯康星州，细胞创伤修复)；(2)与金石公园(耶鲁大学和南加州大学)和Andre Levchenko(耶鲁大学)，细胞与细胞外基质相互作用；(3)与Cal Roskelley(UBC)和Arnold Hayer(McGill)，关于体外细胞-细胞碰撞；与Paul Kulesa(Stowers，神经冠细胞)和喜悦·里曼(UBC)，关于细胞集体迁移和形态发生。HQP的跨学科研究培训将在所有级别进行，从本科生到研究生和博士后，都有很强的EDI组成部分。我的主要目标是一方面将亚细胞信号与单个细胞、细胞组和组织的行为联系起来，另一方面在抽象数学和具体应用之间架起桥梁。