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

化学和机械细胞相互作用在生物体的整个生命周期中发挥作用，并驱动受精卵向成熟成虫的转化。理解这种复杂转变的有效方法是通过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3-D的单个细胞为基础的模型（ICBM）研究这些基本的相互作用，使用三种不同的模型系统。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，但总的来说，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，这些见解扩展了模型的适用性，以更好地理解其他生物系统。 (1)后侧线（posterior lateral line，pLL）是鱼类发育早期形成的感觉系统（用于检测水流）。我将使用洲际弹道导弹来了解pLL原基的极化是如何在pLL发育的早期阶段建立的，并通过模拟关键信号（即Wnt/FGF），我将确定小信号分子（例如趋化因子SDF 1a）如何驱动集体向尾部迁移。我还将模拟化学相互作用（例如，Wnt，FGF，Notch），导致分化和建立的神经肥大，鱼的感觉器官，工作，这将有助于阐明潜在的机制，这是共享的其他脊椎动物。 (2)乳腺癌细胞使用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。我将用我的洲际弹道导弹来建模，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侵袭的。将使用体外和体内实验的数据对模型和预测进行测试。我的研究结果将对其他旁分泌信号系统产生影响，例如伤口愈合中巨噬细胞和结缔组织细胞（例如成纤维细胞）之间的信号系统。 (3)“EMT”是一种过程，其中在衬于表面的组织如皮肤（即上皮细胞）中发现的非运动细胞经历多种分子变化，失去与其它细胞的附着并获得运动间充质细胞特征。EMT在发育过程中的细胞分化中起着至关重要的作用，也参与组织修复，产生间充质细胞，如成纤维细胞。我将使用我的洲际弹道导弹来模拟和探索粘附和信号分子表达的变化，这些分子是启动上皮细胞层中ETM的充分和必要条件。从细胞和发育的角度以及从疾病预防的角度来看，这些机制是重要的。

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.