3-D modelling of cell signalling and motility of tumour cells, epithelial tissues and zebrafish morphogenesis.

肿瘤细胞、上皮组织和斑马鱼形态发生的细胞信号传导和运动的 3-D 建模。

• 批准号: RGPIN-2016-04625
• 负责人: Palsson, Eirikur
• 金额: $ 2.26万
• 依托单位: Simon Fraser University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=709405
• 关键词: modelling; cell; signalling; motility; tumour

Chemical and mechanical cell interactions operate throughout the lifespan of an organism and drive the transformation of a fertilized egg to a mature adult. An effective approach to understanding this complex transformation is through the development and use of mathematical models and computer simulations of these interactions. I propose to use a 3-D individual cell based model (ICBM) to study some of these basic interactions using three different model systems. Each study will answer questions related to the particular model system being investigated, but taken together, the research will advance our knowledge of how cell signaling, cell differentiation and cell adhesion work together during developmental processes to form mature structures. Moreover, such insights expand the applicability of the model to better understand other biological systems. (1) The posterior lateral line (pLL) is a sensory system (for detecting water flow) formed early in fish development. I will use the ICBM to understand how polarization of the pLL primordium is set up in early stages of pLL development and, by modeling key signals (i.e. Wnt/FGF), I will determine how small signaling molecules (e.g. the chemokine SDF1a) drive collective migration toward the tail. I will also model the chemical interactions (e.g., Wnt, FGF, Notch) that lead to differentiation and establishment of the neuromast, a sensory organ of the fish, work that will help elucidate the underlying mechanism, which is shared among other vertebrates. (2) Mammary tumor cells use an EGF/CSF-1 paracrine signaling system to signal to immune system cells called macrophages and coax them to open up passages into blood vessels. I will use my ICBM to model and to understand how this signaling operates and how it enhances tumor cell invasion. The model and predictions will be tested using data from both in vitro and in vivo experiments. My results will have implications for other paracrine signaling systems, such as between macrophages and connective tissue cells (e.g. fibroblasts) in wound healing. (3) EMT' is a process where a non-motile cell found in the tissues that line surfaces, such as the skin (i.e. an epithelial cell) undergoes multiple molecular changes, loses attachment to other cells and acquires a motile mesenchymal cell characteristic. EMTs play crucial roles in cell differentiation during development and are also involved in tissue repair, producing mesenchymal cells such as fibroblasts. I will use my ICBM to model and explore the changes in expression of adhesion and signaling molecules that are sufficient and necessary to initiate ETM in an epithelial cell layer. These mechanisms are important from a cell and developmental perspective, as well as from a disease prevention angle.

化学和机械细胞相互作用贯穿生物体的整个生命周期，并推动受精卵向成熟成体的转变。理解这一复杂转变的有效方法是开发和使用这些相互作用的数学模型和计算机模拟。我建议使用一个基于3-D单个细胞的模型(ICBM)来研究使用三个不同的模型系统的一些基本的相互作用。每项研究都将回答与正在研究的特定模型系统有关的问题，但综合起来，这些研究将增进我们对细胞信号、细胞分化和细胞黏附如何在发育过程中共同作用以形成成熟结构的了解。此外，这种洞察力扩大了该模型的适用性，以更好地理解其他生物系统。 (1)后侧线(PLL)是鱼类发育早期形成的一种感觉系统(用于探测水流)。我将使用ICBM来了解PLL原基的极化是如何在PLL发育的早期阶段建立的，并通过对关键信号(即WNT/FGF)进行建模，我将确定小信号分子(例如趋化因子SDF1a)如何驱动集体向尾部迁移。我还将模拟导致神经肥大分化和建立的化学相互作用(例如，Wnt、FGF、Notch)，这项工作将有助于阐明潜在的机制，这在其他脊椎动物中是相同的。 (2)乳腺肿瘤细胞使用EGF/CSF-1旁分泌信号系统向称为巨噬细胞的免疫系统细胞发出信号，并诱使它们打开进入血管的通道。我将使用我的ICBM来建模，并了解这种信号是如何运作的，以及它是如何增强肿瘤细胞的侵袭的。该模型和预测将使用来自体外和体内实验的数据进行测试。我的结果将对伤口愈合中巨噬细胞和结缔组织细胞(如成纤维细胞)之间的其他旁分泌信号系统产生影响。 (3)EMT是指在皮肤等表面的组织中发现的非运动性细胞经历多个分子变化，失去与其他细胞的附着，获得运动性间充质细胞特征的过程。EMT在发育过程中的细胞分化过程中起着至关重要的作用，也参与组织修复，产生成纤维细胞等间充质细胞。我将使用我的ICBM来模拟和探索黏附和信号分子表达的变化，这些分子是启动上皮细胞层ETM的充分和必要的。从细胞和发育的角度以及从疾病预防的角度来看，这些机制都很重要。