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: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=615192
• 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.

化学和机械的细胞相互作用贯穿于生物体的整个生命周期，并推动受精卵向成熟成人的转变。理解这种复杂转换的有效方法是通过开发和使用数学模型和计算机模拟这些相互作用。我建议使用基于3-D个体细胞的模型（ICBM）来研究使用三种不同模型系统的一些基本相互作用。每项研究都将回答与正在研究的特定模型系统相关的问题，但综合起来，这项研究将推进我们对细胞信号传导、细胞分化和细胞粘附在发育过程中如何共同作用以形成成熟结构的认识。此外，这种见解扩大了模型的适用性，以更好地理解其他生物系统。